bims-mitdis Biomed News
on Mitochondrial disorders
Issue of 2024–01–14
78 papers selected by
Catalina Vasilescu, Helmholz Munich
  1. eIF5A controls mitoprotein import by relieving ribosome stalling at the TIM50 translocase mRNA.
  2. Accessory subunit NDUFB4 participates in mitochondrial complex I supercomplex formation.
  3. METTL17 is an Fe-S cluster checkpoint for mitochondrial translation.
  4. Cristae shaping and dynamics in mitochondrial function.
  5. Control of NAD+ homeostasis by autophagic flux modulates mitochondrial and cardiac function.
  6. Genomics landscape of mitochondrial DNA variations in patients from South Italy affected by mitochondriopathies.
  7. Whole-genome long-read sequencing downsampling and its effect on variant-calling precision and recall.
  8. Emerging roles of mitochondrial functions and epigenetic changes in the modulation of stem cell fate.
  9. Identification of TMEM126A as OXA1L-interacting protein reveals cotranslational quality control in mitochondria.
  10. Simultaneous assessment of mitochondrial DNA copy number and nuclear epigenetic age towards predictive models of development and aging.
  11. Mitochondrial Protein SLIRP Affects Biosynthesis of Cytochrome c Oxidase Subunits in HEK293T Cells.
  12. Mitochondrial phospholipid transport: Role of contact sites and lipid transport proteins.
  13. Empowering mitochondrial metabolism: Exploring L-lactate supplementation as a promising therapeutic approach for metabolic syndrome.
  14. Huntington disease affects mitochondrial network dynamics predisposing to pathogenic mtDNA mutations.
  15. Psychosocial issues and coping strategies in families affected by long-chain fatty acid oxidation disorders.
  16. Biochemical characterization on muscle tissue of a novel biallelic ACO2 mutation in an infant with progressive encephalopathy.
  17. Association between glaucoma susceptibility with combined defects in mitochondrial oxidative phosphorylation and fatty acid beta oxidation.
  18. Brown adipose tissue CoQ deficiency activates the integrated stress response and FGF21-dependent mitohormesis.
  19. Hypoxia and intra-complex genetic suppressors rescue complex I mutants by a shared mechanism.
  20. The mediating role of inflammaging between mitochondrial dysfunction and sarcopenia in aging: a review.
  21. Upregulated pexophagy limits the capacity of selective autophagy.
  22. Liver ACSM3 deficiency mediates metabolic syndrome via a lauric acid-HNF4α-p38 MAPK axis.
  23. Unveiling the Intercompartmental Signaling Axis: Mitochondrial to ER Stress Response (MERSR) and its Impact on Proteostasis.
  24. Augmented mitochondrial apoptotic signaling impairs C2C12 myoblast differentiation following cellular aging through sequential passaging.
  25. Lipid peroxidation does not mediate muscle atrophy induced by PSD deficiency.
  26. High-dimensional phenotyping to define the genetic basis of cellular morphology.
  27. DHCR24-mediated sterol homeostasis during spermatogenesis is required for sperm mitochondrial sheath formation and impacts male fertility over time.
  28. Effects of aging on glucose and lipid metabolism in mice.
  29. Molecular Mechanisms of Neuroprotection by Ketone Bodies and Ketogenic Diet in Cerebral Ischemia and Neurodegenerative Diseases.
  30. Sulfur Amino Acid Restriction alters mitochondrial function depending on tissue, sex, and Methionine sulfoxide reductase A (MsrA) status.
  31. Human telomere length is chromosome specific and conserved across individuals.
  32. Mitochondrial Targeting against Alzheimer's Disease: Lessons from Hibernation.
  33. NDV inhibited IFN-β secretion through impeding CHCHD10-mediated mitochondrial fusion to promote viral proliferation.
  34. Developmental changes of the mitochondria in the murine anteroventral cochlear nucleus.
  35. Loss of Function of the Cytoplasmic Fe-S Assembly Protein CIAO1 Causes a Neuromuscular Disorder with Compromise of Nucleocytoplasmic Fe-S Enzymes.
  36. Systems-level analyses dissociate genetic regulators of reactive oxygen species and energy production.
  37. Evaluating ClinGen variant curation expert panels' application of PVS1 code.
  38. Exogenous mitochondrial transfer increases energy expenditure and attenuates adiposity gains in mice with diet-induced obesity.
  39. Interleukin-6-elicited chronic neuroinflammation may decrease survival but is not sufficient to drive disease progression in a mouse model of Leigh syndrome.
  40. Microbiome metabolite quantification methods enabling insights into human health and disease.
  41. Rare disease gene association discovery from burden analysis of the 100,000 Genomes Project data.
  42. Contributing roles of mitochondrial dysfunction and hepatocyte apoptosis in liver diseases through oxidative stress, post-translational modifications, inflammation, and intestinal barrier dysfunction.
  43. Ironing out the mitochondria.
  44. MAGPIE: accurate pathogenic prediction for multiple variant types using machine learning approach.
  45. CircPTEN-MT from PTEN regulates mitochondrial energy metabolism.
  46. Electro-metabolic signaling.
  47. Assessing the quality and value of metabolic chart data for capturing core outcomes for pediatric medium-chain acyl-CoA dehydrogenase (MCAD) deficiency.
  48. The mitochondrial genome-encoded peptide MOTS-c interacts with Bcl-2 to alleviate nonalcoholic steatohepatitis progression.
  49. Insights into neuroinflammatory mechanisms of deep brain stimulation in Parkinson's disease.
  50. Berberine Induces Mitophagy through Adenosine Monophosphate-Activated Protein Kinase and Ameliorates Mitochondrial Dysfunction in PINK1 Knockout Mouse Embryonic Fibroblasts.
  51. O-GlcNAc regulates the mitochondrial integrated stress response by regulating ATF4.
  52. Age and dietary restriction modulate mitochondrial quality in quadriceps femoris muscle of male mice.
  53. Pyruvate carboxylase deficiency type C; variable presentation and beneficial effect of triheptanoin.
  54. A new GUV-based assay to reconstitute membrane tethering in vitro demonstrates the vesicle tethering ability of the selective autophagy scaffold Atg11.
  55. Niacin - a scoping review for Nordic Nutrition Recommendations 2023.
  56. TIME-seq reduces time and cost of DNA methylation measurement for epigenetic clock construction.
  57. DMHPpp1r17 neurons regulate aging and lifespan in mice through hypothalamic-adipose inter-tissue communication.
  58. Detection of hidden intronic DDC variant in aromatic L-amino acid decarboxylase deficiency by adaptive sampling.
  59. A guidebook of spatial transcriptomic technologies, data resources and analysis approaches.
  60. DL-SPhos: Prediction of serine phosphorylation sites using transformer language model.
  61. Glyoxylate reductase: Definitive identification in human liver mitochondria, its importance for the compartment-specific detoxification of glyoxylate.
  62. Cell type-specific enrichment of somatic aneuploidy in the mammalian brain.
  63. Unbiased phenotype and genotype matching maximizes gene discovery and diagnostic yield.
  64. Reanalysis of genomic data, how do we do it now and what if we automate it? A qualitative study.
  65. Cockayne syndrome: A pediatric neurodegenerative disorder linking mitochondria to aging.
  66. Longevity control by supersulfide-mediated mitochondrial respiration and regulation of protein quality.
  67. Further delineation of the phenotypic and metabolomic profile of ALDH1L2-related neurodevelopmental disorder.
  68. Mitochondrial dysfunction in the pathogenesis of acute pancreatitis.
  69. Protecting Patients by Reducing Diagnostic Error.
  70. Stay in touch with the endoplasmic reticulum.
  71. Analysis of rare Parkinson's disease variants in millions of people.
  72. IUPHAR ECR review: The cGAS-STING pathway: novel functions beyond innate immune and emerging therapeutic opportunities.
  73. Secretome Analyses Identify FKBP4 as a GBA1-Associated Protein in CSF and iPS Cells from Parkinson's Disease Patients with GBA1 Mutations.
  74. SIGMA leverages protein structural information to predict the pathogenicity of missense variants.
  75. Progressive encephalopathy after routine 4-month immunizations in a patient with NAXD genetic variant.
  76. Newborn screening for fatty acid oxidation disorders in a southern Chinese population.
  77. Shifting the trajectory of therapeutic development for neurological and psychiatric disorders.
  78. TALK-1-mediated alterations of β-cell mitochondrial function and insulin secretion impair glucose homeostasis on a diabetogenic diet.
  1. bioRxiv. 2023 Dec 19. pii: 2023.12.19.572290. [Epub ahead of print]
    eIF5A controls mitoprotein import by relieving ribosome stalling at the TIM50 translocase mRNA.
    Marina Barba-Aliaga, Vanessa Bernal, Cynthia Rong, Brian M Zid, Paula Alepuz.
      The efficient import of nuclear-encoded proteins into mitochondria is crucial for proper mitochondrial function. The conserved translation factor eIF5A is primarily known as an elongation factor which binds ribosomes to alleviate ribosome stalling at sequences encoding polyprolines or combinations of proline with glycine and charged amino acids. eIF5A is known to impact the mitochondrial function across a variety of species although the precise molecular mechanism underlying this impact remains unclear. We found that depletion of eIF5A in yeast drives reduced translation and levels of TCA cycle and oxidative phosphorylation proteins. We further found that loss of eIF5A leads to the accumulation of mitoprotein precursors in the cytosol as well as to the induction of a mitochondrial import stress response. Here we identify an essential polyproline-containing protein as a direct eIF5A target for translation: the mitochondrial inner membrane protein Tim50, which is the receptor sub-unit of the TIM23 translocase complex. We show how eIF5A directly controls mitochondrial protein import through the alleviation of ribosome stalling along TIM50 mRNA at the mitochondrial surface. Removal of the polyprolines from Tim50 rescues the mitochondrial import stress response, as well as the translation of oxidative phosphorylation reporter genes in an eIF5A loss of function. Overall, our findings elucidate how eIF5A impacts the mitochondrial function by reducing ribosome stalling and facilitating protein translation, thereby positively impacting the mitochondrial import process.
    DOI:  https://doi.org/10.1101/2023.12.19.572290
  2. J Biol Chem. 2024 Jan 08. pii: S0021-9258(24)00002-4. [Epub ahead of print] 105626
    Accessory subunit NDUFB4 participates in mitochondrial complex I supercomplex formation.
    Gaganvir Parmar, Claire Fong-McMaster, Chantal Pileggi, David A Patten, Alexanne Cuillerier, Stephanie Myers, Ying Wang, Siegfried Hekimi, Miroslava Cuperlovic-Culf, Mary-Ellen Harper.
      Mitochondrial electron transport chain (ETC) complexes organize into supramolecular structures called respiratory supercomplexes (SCs). The role of respiratory SC remains largely unconfirmed despite evidence supporting their necessity for mitochondrial respiratory function. The mechanisms underlying the formation of the I1III2IV1 "respirasome" SC are also not fully understood, further limiting insights into these processes in physiology and diseases, including neurodegeneration and metabolic syndromes. NDUFB4 is a complex I accessory subunit that contains residues that interact with the subunit UQCRC1 from complex III, suggesting that NDUFB4 is integral for I1III2IV1 respirasome integrity. Here, we introduced specific point mutations to Asn24 (N24) and Arg30 (R30) residues on NDUFB4 to decipher the role of I1III2-containing respiratory SCs in cellular metabolism while minimizing the functional consequences to complex I assembly. Our results demonstrate that NDUFB4 point mutations N24A and R30A impair I1III2IV1 respirasome assembly and reduce mitochondrial respiratory flux. Steady-state metabolomics also revealed a global decrease in TCA cycle metabolites, affecting NADH-generating substrates. Taken together, our findings highlight an integral role of NDUFB4 in respirasome assembly and demonstrate the functional significance of SCs in regulating mammalian cell bioenergetics.
    Keywords:  Mitochondria; NDUFB4; electron transport chain; oxidative phosphorylation; respirasome; steady-state metabolomics; supercomplexes
    DOI:  https://doi.org/10.1016/j.jbc.2024.105626
  3. Mol Cell. 2024 Jan 04. pii: S1097-2765(23)01035-3. [Epub ahead of print]
    METTL17 is an Fe-S cluster checkpoint for mitochondrial translation.
    Tslil Ast, Yuzuru Itoh, Shayan Sadre, Jason G McCoy, Gil Namkoong, Jordan C Wengrod, Ivan Chicherin, Pallavi R Joshi, Piotr Kamenski, Daniel L M Suess, Alexey Amunts, Vamsi K Mootha.
      Friedreich's ataxia (FA) is a debilitating, multisystemic disease caused by the depletion of frataxin (FXN), a mitochondrial iron-sulfur (Fe-S) cluster biogenesis factor. To understand the cellular pathogenesis of FA, we performed quantitative proteomics in FXN-deficient human cells. Nearly every annotated Fe-S cluster-containing protein was depleted, indicating that as a rule, cluster binding confers stability to Fe-S proteins. We also observed depletion of a small mitoribosomal assembly factor METTL17 and evidence of impaired mitochondrial translation. Using comparative sequence analysis, mutagenesis, biochemistry, and cryoelectron microscopy, we show that METTL17 binds to the mitoribosomal small subunit during late assembly and harbors a previously unrecognized [Fe4S4]2+ cluster required for its stability. METTL17 overexpression rescued the mitochondrial translation and bioenergetic defects, but not the cellular growth, of FXN-depleted cells. These findings suggest that METTL17 acts as an Fe-S cluster checkpoint, promoting translation of Fe-S cluster-rich oxidative phosphorylation (OXPHOS) proteins only when Fe-S cofactors are replete.
    Keywords:  FA; Fe-S cluster; Friedreich’s ataxia; METTL17; frataxin; mitochondria; mitoribosome
    DOI:  https://doi.org/10.1016/j.molcel.2023.12.016
  4. J Cell Sci. 2024 Jan 01. pii: jcs260986. [Epub ahead of print]137(1):
    Cristae shaping and dynamics in mitochondrial function.
    Claire Caron, Giulia Bertolin.
      Mitochondria are multifunctional organelles of key importance for cell homeostasis. The outer mitochondrial membrane (OMM) envelops the organelle, and the inner mitochondrial membrane (IMM) is folded into invaginations called cristae. As cristae composition and functions depend on the cell type and stress conditions, they recently started to be considered as a dynamic compartment. A number of proteins are known to play a role in cristae architecture, such as OPA1, MIC60, LETM1, the prohibitin (PHB) complex and the F1FO ATP synthase. Furthermore, phospholipids are involved in the maintenance of cristae ultrastructure and dynamics. The use of new technologies, including super-resolution microscopy to visualize cristae dynamics with superior spatiotemporal resolution, as well as high-content techniques and datasets have not only allowed the identification of new cristae proteins but also helped to explore cristae plasticity. However, a number of open questions remain in the field, such as whether cristae-resident proteins are capable of changing localization within mitochondria, or whether mitochondrial proteins can exit mitochondria through export. In this Review, we present the current view on cristae morphology, stability and composition, and address important outstanding issues that might pave the way to future discoveries.
    Keywords:  Cristae; Cristae dynamics; High-content approaches; Mitochondria; Quantitative microscopy
    DOI:  https://doi.org/10.1242/jcs.260986
  5. EMBO J. 2024 Jan 11.
    Control of NAD+ homeostasis by autophagic flux modulates mitochondrial and cardiac function.
    Quanjiang Zhang, Zhonggang Li, Qiuxia Li, Samuel Aj Trammell, Mark S Schmidt, Karla Maria Pires, Jinjin Cai, Yuan Zhang, Helena Kenny, Sihem Boudina, Charles Brenner, E Dale Abel.
      Impaired autophagy is known to cause mitochondrial dysfunction and heart failure, in part due to altered mitophagy and protein quality control. However, whether additional mechanisms are involved in the development of mitochondrial dysfunction and heart failure in the setting of deficient autophagic flux remains poorly explored. Here, we show that impaired autophagic flux reduces nicotinamide adenine dinucleotide (NAD+) availability in cardiomyocytes. NAD+ deficiency upon autophagic impairment is attributable to the induction of nicotinamide N-methyltransferase (NNMT), which methylates the NAD+ precursor nicotinamide (NAM) to generate N-methyl-nicotinamide (MeNAM). The administration of nicotinamide mononucleotide (NMN) or inhibition of NNMT activity in autophagy-deficient hearts and cardiomyocytes restores NAD+ levels and ameliorates cardiac and mitochondrial dysfunction. Mechanistically, autophagic inhibition causes the accumulation of SQSTM1, which activates NF-κB signaling and promotes NNMT transcription. In summary, we describe a novel mechanism illustrating how autophagic flux maintains mitochondrial and cardiac function by mediating SQSTM1-NF-κB-NNMT signaling and controlling the cellular levels of NAD+.
    Keywords:  Autophagic Flux; Heart Dysfunction; Mitochondrial Homeostasis; NAD+ Metabolism
    DOI:  https://doi.org/10.1038/s44318-023-00009-w
  6. J Neurol Sci. 2024 Jan 06. pii: S0022-510X(24)00004-2. [Epub ahead of print]457 122869
    Genomics landscape of mitochondrial DNA variations in patients from South Italy affected by mitochondriopathies.
    Luigi Citrigno, Antonio Qualtieri, Annamaria Cerantonio, Selene De Benedittis, Olivier Gallo, Gemma Di Palma, Patrizia Spadafora, Francesca Cavalcanti.
      Mitochondrial DNA (mtDNA) is a 16,569 base pairs, double-stranded, circular molecule that contains 37 genes coding for 13 subunits of the respiratory chain plus 2 rRNAs and 22 tRNAs. Mutations in these genes have been identified in patients with a variety of disorders affecting every system in the body. The advent of next generation sequencing technologies has provided the possibility to perform the whole mitochondrial DNA sequencing, allowing the identification of disease-causing pathogenic variants in a single platform. In this study, the whole mtDNA of 100 patients from South Italy affected by mitochondrial diseases was analyzed by using an amplicon-based approach and then the enriched libraries were deeply sequenced on the ION Torrent platform (Thermofisher Scientific Waltham, MA, USA). After bioinformatics analysis and filtering, we were able to find 26 nonsynonymous variants with a MAF <1% that were associated with different pathological phenotypes, expanding the mutational spectrum of these diseases. Moreover, among the new mutations found, we have also analyzed the 3D structure of the MT-ATP6 A200T gene variation in order to confirm suspected functional alterations. This work brings light on new variants possibly associated with several mitochondriopathies in patients from South Italy and confirms that deep sequencing approach, compared to the standard methods, is a reliable and time-cost reducing strategy to detect all the variants present in the mitogenome, making the possibility to create a genomics landscape of mitochondrial DNA variations in human diseases.
    Keywords:  Deep sequencing; Mitochondrial DNA; Molecular signature; Protein 3D structure molecular analysis
    DOI:  https://doi.org/10.1016/j.jns.2024.122869
  7. Genome Res. 2023 Dec 27. 33(12): 2029-2040
    Whole-genome long-read sequencing downsampling and its effect on variant-calling precision and recall.
    William T Harvey, Peter Ebert, Jana Ebler, Peter A Audano, Katherine M Munson, Kendra Hoekzema, David Porubsky, Christine R Beck, Tobias Marschall, Kiran Garimella, Evan E Eichler.
      Advances in long-read sequencing (LRS) technologies continue to make whole-genome sequencing more complete, affordable, and accurate. LRS provides significant advantages over short-read sequencing approaches, including phased de novo genome assembly, access to previously excluded genomic regions, and discovery of more complex structural variants (SVs) associated with disease. Limitations remain with respect to cost, scalability, and platform-dependent read accuracy and the tradeoffs between sequence coverage and sensitivity of variant discovery are important experimental considerations for the application of LRS. We compare the genetic variant-calling precision and recall of Oxford Nanopore Technologies (ONT) and Pacific Biosciences (PacBio) HiFi platforms over a range of sequence coverages. For read-based applications, LRS sensitivity begins to plateau around 12-fold coverage with a majority of variants called with reasonable accuracy (F1 score above 0.5), and both platforms perform well for SV detection. Genome assembly increases variant-calling precision and recall of SVs and indels in HiFi data sets with HiFi outperforming ONT in quality as measured by the F1 score of assembly-based variant call sets. While both technologies continue to evolve, our work offers guidance to design cost-effective experimental strategies that do not compromise on discovering novel biology.
    DOI:  https://doi.org/10.1101/gr.278070.123
  8. Cell Mol Life Sci. 2024 Jan 12. 81(1): 26
    Emerging roles of mitochondrial functions and epigenetic changes in the modulation of stem cell fate.
    Chensong Zhang, Yang Meng, Junhong Han.
      Mitochondria serve as essential organelles that play a key role in regulating stem cell fate. Mitochondrial dysfunction and stem cell exhaustion are two of the nine distinct hallmarks of aging. Emerging research suggests that epigenetic modification of mitochondria-encoded genes and the regulation of epigenetics by mitochondrial metabolites have an impact on stem cell aging or differentiation. Here, we review how key mitochondrial metabolites and behaviors regulate stem cell fate through an epigenetic approach. Gaining insight into how mitochondria regulate stem cell fate will help us manufacture and preserve clinical-grade stem cells under strict quality control standards, contributing to the development of aging-associated organ dysfunction and disease.
    Keywords:  Epigenetic modifications; Mitochondria; Mitochondria metabolites; Senescence; Stem cell fate
    DOI:  https://doi.org/10.1007/s00018-023-05070-6
  9. Mol Cell. 2023 Dec 29. pii: S1097-2765(23)01031-6. [Epub ahead of print]
    Identification of TMEM126A as OXA1L-interacting protein reveals cotranslational quality control in mitochondria.
    Sabine Poerschke, Silke Oeljeklaus, Luis Daniel Cruz-Zaragoza, Alexander Schenzielorz, Drishan Dahal, Hauke Sven Hillen, Hirak Das, Laura Sophie Kremer, Anusha Valpadashi, Mirjam Breuer, Johannes Sattmann, Ricarda Richter-Dennerlein, Bettina Warscheid, Sven Dennerlein, Peter Rehling.
      Cellular proteostasis requires transport of polypeptides across membranes. Although defective transport processes trigger cytosolic rescue and quality control mechanisms that clear translocases and membranes from unproductive cargo, proteins that are synthesized within mitochondria are not accessible to these mechanisms. Mitochondrial-encoded proteins are inserted cotranslationally into the inner membrane by the conserved insertase OXA1L. Here, we identify TMEM126A as a OXA1L-interacting protein. TMEM126A associates with mitochondrial ribosomes and translation products. Loss of TMEM126A leads to the destabilization of mitochondrial translation products, triggering an inner membrane quality control process, in which newly synthesized proteins are degraded by the mitochondrial iAAA protease. Our data reveal that TMEM126A cooperates with OXA1L in protein insertion into the membrane. Upon loss of TMEM126A, the cargo-blocked OXA1L insertase complexes undergo proteolytic clearance by the iAAA protease machinery together with its cargo.
    Keywords:  mitochondria; mitochondrial quality control; mitochondrial translation
    DOI:  https://doi.org/10.1016/j.molcel.2023.12.013
  10. BMC Res Notes. 2024 Jan 11. 17(1): 21
    Simultaneous assessment of mitochondrial DNA copy number and nuclear epigenetic age towards predictive models of development and aging.
    Phyo W Win, Julia Nyugen, Amanda L Morin, Charles E Newcomb, Shiva M Singh, Noha Gomaa, Christina A Castellani.
       OBJECTIVE: Mitochondrial dysfunction and nuclear epigenetic alterations, two hallmarks of aging, are associated with aberrant development and complex disease risk. Here, we report a method for the simultaneous assessment of mitochondrial DNA copy number (mtDNA-CN) and DNA methylation age (DNAm age) from the same DNA extraction using quantitative polymerase chain reaction (qPCR) and array data, respectively.
    RESULT: We present methods for the concurrent estimation of mtDNA-CN and DNAm age from the same DNA samples. This includes qPCR to estimate mtDNA-CN, representing the number of circular mitochondrial genomes in a cell, and DNA methylation microarray data to estimate the epigenetic age of an individual. Further, we provide a method for the combination of these metrics into a shared metric termed 'mtEpiAge'. This approach provides a valuable tool for exploring the interplay between mitochondrial dysfunction and nuclear epigenetic alterations, and their associations with disease and aging.
    Keywords:  DNA methylation; Epigenetic age; Mitochondrial DNA; Mitochondrial DNA copy number; qPCR
    DOI:  https://doi.org/10.1186/s13104-023-06673-9
  11. Int J Mol Sci. 2023 Dec 20. pii: 93. [Epub ahead of print]25(1):
    Mitochondrial Protein SLIRP Affects Biosynthesis of Cytochrome c Oxidase Subunits in HEK293T Cells.
    Mariia V Baleva, Uliana Piunova, Ivan Chicherin, Ruslan Vasilev, Sergey Levitskii, Piotr Kamenski.
      Mitochondria carry out various vital roles in eukaryotic cells, including ATP energy synthesis, the regulation of apoptosis, Fe-S cluster formation, and the metabolism of fatty acids, amino acids, and nucleotides. Throughout evolution, mitochondria lost most of their ancestor's genome but kept the replication, transcription, and translation machinery. Protein biosynthesis in mitochondria is specialized in the production of highly hydrophobic proteins encoded by mitochondria. These proteins are components of oxidative phosphorylation chain complexes. The coordination of protein synthesis must be precise to ensure the correct assembly of nuclear-encoded subunits for these complexes. However, the regulatory mechanisms of mitochondrial translation in human cells are not yet fully understood. In this study, we examined the contribution of the SLIRP protein in regulating protein biosynthesis in mitochondria. Using a click-chemistry approach, we discovered that deletion of the SLIRP gene disturbs mitochondrial translation, leading to the dysfunction of complexes I and IV, but it has no significant effect on complexes III and V. We have shown that this protein interacts only with the small subunit of the mitochondrial ribosome, which may indicate its involvement in the regulation of the mitochondrial translation initiation stage.
    Keywords:  mitochondria; translation; translation regulation
    DOI:  https://doi.org/10.3390/ijms25010093
  12. Prog Lipid Res. 2024 Jan 07. pii: S0163-7827(24)00001-8. [Epub ahead of print]94 101268
    Mitochondrial phospholipid transport: Role of contact sites and lipid transport proteins.
    Vijay Aditya Mavuduru, Lavanya Vadupu, Krishna Kanta Ghosh, Sabyasachi Chakrabortty, Balázs Gulyás, Parasuraman Padmanabhan, Writoban Basu Ball.
      One of the major constituents of mitochondrial membranes is the phospholipids, which play a key role in maintaining the structure and the functions of the mitochondria. However, mitochondria do not synthesize most of the phospholipids in situ, necessitating the presence of phospholipid import pathways. Even for the phospholipids, which are synthesized within the inner mitochondrial membrane (IMM), the phospholipid precursors must be imported from outside the mitochondria. Therefore, the mitochondria heavily rely on the phospholipid transport pathways for its proper functioning. Since, mitochondria are not part of a vesicular trafficking network, the molecular mechanisms of how mitochondria receive its phospholipids remain a relevant question. One of the major ways that hydrophobic phospholipids can cross the aqueous barrier of inter or intraorganellar spaces is by apposing membranes, thereby decreasing the distance of transport, or by being sequestered by lipid transport proteins (LTPs). Therefore, with the discovery of LTPs and membrane contact sites (MCSs), we are beginning to understand the molecular mechanisms of phospholipid transport pathways in the mitochondria. In this review, we will present a brief overview of the recent findings on the molecular architecture and the importance of the MCSs, both the intraorganellar and interorganellar contact sites, in facilitating the mitochondrial phospholipid transport. In addition, we will also discuss the role of LTPs for trafficking phospholipids through the intermembrane space (IMS) of the mitochondria. Mechanistic insights into different phospholipid transport pathways of mitochondria could be exploited to vary the composition of membrane phospholipids and gain a better understanding of their precise role in membrane homeostasis and mitochondrial bioenergetics.
    Keywords:  ERMES; Mitochondria; Mitochondrial contact sites; Phospholipid biosynthesis; Phospholipid transport; vCLAMP
    DOI:  https://doi.org/10.1016/j.plipres.2024.101268
  13. Metabolism. 2024 Jan 10. pii: S0026-0495(24)00013-1. [Epub ahead of print] 155787
    Empowering mitochondrial metabolism: Exploring L-lactate supplementation as a promising therapeutic approach for metabolic syndrome.
    Ming Cai, Shuyao Li, Keren Cai, Xinlin Du, Jia Han, Jingyun Hu.
      Mitochondrial dysfunction plays a critical role in the pathogenesis of metabolic syndrome (MetS), affecting various cell types and organs. In MetS animal models, mitochondria exhibit decreased quality control, characterized by abnormal morphological structure, impaired metabolic activity, reduced energy production, disrupted signaling cascades, and oxidative stress. The aberrant changes in mitochondrial function exacerbate the progression of metabolic syndrome, setting in motion a pernicious cycle. From this perspective, reversing mitochondrial dysfunction is likely to become a novel and powerful approach for treating MetS. Unfortunately, there are currently no effective drugs available in clinical practice to improve mitochondrial function. Recently, L-lactate has garnered significant attention as a valuable metabolite due to its ability to regulate mitochondrial metabolic processes and function. It is highly likely that treating MetS and its related complications can be achieved by correcting mitochondrial homeostasis disorders. In this review, we comprehensively discuss the complex relationship between mitochondrial function and MetS and the involvement of L-lactate in regulating mitochondrial metabolism and associated signaling pathways. Furthermore, it highlights recent findings on the involvement of L-lactate in common pathologies of MetS and explores its potential clinical application and further prospects, thus providing new insights into treatment possibilities for MetS.
    Keywords:  L-lactate; Metabolic syndrome; Mitochondrial function; Mitochondrial metabolism
    DOI:  https://doi.org/10.1016/j.metabol.2024.155787
  14. Brain. 2024 Jan 09. pii: awae007. [Epub ahead of print]
    Huntington disease affects mitochondrial network dynamics predisposing to pathogenic mtDNA mutations.
    Andreas Neueder, Kerstin Kojer, Zhenglong Gu, Yiqin Wang, Tanja Hering, Sarah Tabrizi, Jan-Willem Taanman, Michael Orth.
      Huntington disease (HD) predominantly affects the brain causing a mixed movement disorder, cognitive decline and behavioural abnormalities. It also causes a peripheral phenotype involving skeletal muscle. Mitochondrial dysfunction has been reported in tissues of HD models, including skeletal muscle, and lymphoblasts and fibroblasts cultures from HD patients. Mutant huntingtin protein (mutHTT) expression can impair mitochondrial quality control and accelerate mitochondrial ageing. Here we obtained fresh human skeletal muscle, a post-mitotic tissue expressing the mutated HTT allele at physiological levels since birth, and primary cell lines from HTT CAG repeat expansion mutation carriers and matched healthy volunteers to examine whether such a mitochondrial phenotype exists in human HD. Using ultra-deep mitochondrial DNA (mtDNA) sequencing, we show an accumulation of mtDNA mutations affecting oxidative phosphorylation. Tissue proteomics indicate impairments in mtDNA maintenance with increased mitochondrial biogenesis of less efficient oxidative phosphorylation (lower complex I and IV activity). In full-length mutHTT expressing primary human cell lines, fission inducing mitochondrial stress resulted in normal mitophagy. In contrast, expression of high levels of N-terminal mutHTT fragments promoted mitochondrial fission and resulted in slower, less dynamic mitophagy. Expression of high levels of mutHTT fragments due to somatic nuclear HTT CAG instability can thus affect mitochondrial network dynamics and mitophagy leading to pathogenic mtDNA mutations. We show that life-long expression of mutant HTT causes a mitochondrial phenotype indicative of mtDNA instability in fresh post-mitotic human skeletal muscle. Thus, genomic instability may not be limited to nuclear DNA where it results in somatic expansion of HTT CAG repeat length in particularly vulnerable cells, such as striatal neurons. In addition to efforts targeting the causative mutation promoting mitochondrial health may be a complementary strategy in treating diseases with DNA instability, such as HD.
    Keywords:  DNA instability; huntingtin fragments; mitochondrial fission; mitophagy; proteomics; ultra-deep mitochondrial DNA sequencing
    DOI:  https://doi.org/10.1093/brain/awae007
  15. JIMD Rep. 2024 Jan;65(1): 25-38
    Psychosocial issues and coping strategies in families affected by long-chain fatty acid oxidation disorders.
    Maren Thiel, Sven F Garbade, Stefanie Rosenbaum-Fabian, Ute Spiekerkoetter, Sarah C Grünert.
      Long-chain fatty acid oxidation disorders (lcFAODs) are associated with a high disease burden due to both the risk of metabolic decompensation as well as chronic, partly irreversible complications in some. Little research has been performed on the impact of these disorders on the daily life of parents and caregivers. We performed a web-based questionnaire study among parents/caregivers of patients affected with lcFAODs. The questionnaire focused on challenges at different ages of the child, on disease management issues, schooling, family and social life as well as the parental job situation, and their overall attitude toward the disease and the future life of their child. Data were collected from parents/caregivers of 63 patients (87 respondents, 63% mothers, 36% fathers) with lcFAODs (median age of patients 8.0 years, range 0-25 years, long-chain 3-hydrocyacyl-CoA dehydrogenase deficiency 40%, mitochondrial trifunctional protein deficiency 14%, very long-chain acyl-CoA dehydrogenase deficiency 41%, carnitine palmitoyltransferase 2 deficiency 5%). The overall disease burden of parents was considered highest during infancy and decreased with increasing age of their child. More than one third of parents were afraid that their child's disease might have an impact on his/her career choice and adult life. Negative effects of the child's disease on the job situation and career development were more commonly reported by mothers compared to fathers. Although the majority of parents considered their child's metabolic disorder a severe disease, most parents had a positive attitude toward their child's disease and seemed to cope well with their situation.
    Keywords:  coping; disease burden; fatty acid oxidation defects; fatty acid oxidation disorders; quality of life
    DOI:  https://doi.org/10.1002/jmd2.12402
  16. JIMD Rep. 2024 Jan;65(1): 3-9
    Biochemical characterization on muscle tissue of a novel biallelic ACO2 mutation in an infant with progressive encephalopathy.
    Federica Silvia Ricci, Serena Stanga, Mariarosa Mezzanotte, Cristina Marinaccio, Rossella D'Alessandro, Alessandra Somà, Stefano Sottemano, Alessandra Conio, Giovanni Morana, Marco Spada, Marina Boido, Tiziana E Mongini.
      The ACO2 gene encodes the mitochondrial protein aconitate hydratase, which is responsible for catalyzing the interconversion of citrate into isocitrate in the tricarboxylic acid (TCA) cycle. Mitochondrial aconitase is expressed ubiquitously, and deficiencies in TCA-cycle enzymes have been reported to cause various neurodegenerative diseases due to disruption of cellular energy metabolism and development of oxidative stress. We investigated a severe early infantile-onset neurometabolic syndrome due to a homozygous novel variant in exon 13 of the ACO2 gene. The in vitro pathogenicity of this variant of unknown significance was demonstrated by the loss of both protein expression and its enzymatic activity on muscle tissue sample taken from the patient. The patient presented with progressive encephalopathy soon after birth, characterized by hypotonia, progressive severe muscle atrophy, and respiratory failure. Serial brain magnetic resonance imaging showed progressive abnormalities compatible with a metabolic disorder, possibly mitochondrial. Muscle biopsy disclosed moderate myopathic alterations and features consistent with a mitochondriopathy albeit nonspecific. The course was characterized by progressive worsening of the clinical and neurological picture, and the patient died at 5 months of age. This study provides the first report on the validation in muscle from human subjects regarding in vitro analysis for mitochondrial aconitase activity. To our knowledge, no prior reports have demonstrated a correlation of phenotypic and diagnostic characteristics with in vitro muscle enzymatic activity of mitochondrial aconitase in humans. In conclusion, this case further expands the genetic spectrum of ACO2 variants and defines a complex case of severe neonatal neurometabolic disorder.
    Keywords:  ACO2 gene; mitochondrial aconitase; neonatal neurometabolic disorder
    DOI:  https://doi.org/10.1002/jmd2.12400
  17. Mol Aspects Med. 2024 Jan 11. pii: S0098-2997(23)00078-X. [Epub ahead of print]96 101238
    Association between glaucoma susceptibility with combined defects in mitochondrial oxidative phosphorylation and fatty acid beta oxidation.
    Zulvikar Syambani Ulhaq, Guido Barbieri Bittencourt, Gita Vita Soraya, Lola Ayu Istifiani, Syafrizal Aji Pamungkas, Yukiko Ogino, Dian Kesumapramudya Nurputra, William Ka Fai Tse.
      Glaucoma is one of the leading causes of visual impairment and blindness worldwide, and is characterized by the progressive damage of retinal ganglion cells (RGCs) and the atrophy of the optic nerve head (ONH). The exact cause of RGC loss and optic nerve damage in glaucoma is not fully understood. The high energy demands of these cells imply a higher sensitivity to mitochondrial defects. Moreover, it has been postulated that the optic nerve is vulnerable towards damage from oxidative stress and mitochondrial dysfunction. To investigate this further, we conducted a pooled analysis of mitochondrial variants related to energy production, specifically focusing on oxidative phosphorylation (OXPHOS) and fatty acid β-oxidation (FAO). Our findings revealed that patients carrying non-synonymous (NS) mitochondrial DNA (mtDNA) variants within the OXPHOS complexes had an almost two-fold increased risk of developing glaucoma. Regarding FAO, our results demonstrated that longer-chain acylcarnitines (AC) tended to decrease, while shorter-chain AC tended to increase in patients with glaucoma. Furthermore, we observed that the knocking down cpt1a (a key rate-limiting enzyme involved in FAO) in zebrafish induced a degenerative process in the optic nerve and RGC, which resembled the characteristics observed in glaucoma. In conclusion, our study provides evidence that genes encoding mitochondrial proteins involved in energy metabolisms, such as OXPHOS and FAO, are associated with glaucoma. These findings contribute to a better understanding of the molecular mechanisms underlying glaucoma pathogenesis and may offer potential targets for therapeutic interventions in the future.
    Keywords:  CPT1; Fatty acid β-oxidation (FAO); Glaucoma; Mitochondrial genes; Oxidative phosphorylation (OXPHOS); Oxidative stress; Zebrafish
    DOI:  https://doi.org/10.1016/j.mam.2023.101238
  18. EMBO J. 2024 Jan 11.
    Brown adipose tissue CoQ deficiency activates the integrated stress response and FGF21-dependent mitohormesis.
    Ching-Fang Chang, Amanda L Gunawan, Irene Liparulo, Peter-James H Zushin, Kaitlyn Vitangcol, Greg A Timblin, Kaoru Saijo, Biao Wang, Güneş Parlakgül, Ana Paula Arruda, Andreas Stahl.
      Coenzyme Q (CoQ) is essential for mitochondrial respiration and required for thermogenic activity in brown adipose tissues (BAT). CoQ deficiency leads to a wide range of pathological manifestations, but mechanistic consequences of CoQ deficiency in specific tissues, such as BAT, remain poorly understood. Here, we show that pharmacological or genetic CoQ deficiency in BAT leads to stress signals causing accumulation of cytosolic mitochondrial RNAs and activation of the eIF2α kinase PKR, resulting in activation of the integrated stress response (ISR) with suppression of UCP1 but induction of FGF21 expression. Strikingly, despite diminished UCP1 levels, BAT CoQ deficiency displays increased whole-body metabolic rates at room temperature and thermoneutrality resulting in decreased weight gain on high-fat diets (HFD). In line with enhanced metabolic rates, BAT and inguinal white adipose tissue (iWAT) interorgan crosstalk caused increased browning of iWAT in BAT-specific CoQ deficient animals. This mitohormesis-like effect depends on the ATF4-FGF21 axis and BAT-secreted FGF21, revealing an unexpected role for CoQ in the modulation of whole-body energy expenditure with wide-ranging implications for primary and secondary CoQ deficiencies.
    Keywords:  Brown Adipose Tissue; Coenzyme Q; FGF21; Mitochondrial Unfolded Protein Response; Mitohormesis
    DOI:  https://doi.org/10.1038/s44318-023-00008-x
  19. Cell. 2024 Jan 05. pii: S0092-8674(23)01342-9. [Epub ahead of print]
    Hypoxia and intra-complex genetic suppressors rescue complex I mutants by a shared mechanism.
    Joshua D Meisel, Maria Miranda, Owen S Skinner, Presli P Wiesenthal, Sandra M Wellner, Alexis A Jourdain, Gary Ruvkun, Vamsi K Mootha.
      The electron transport chain (ETC) of mitochondria, bacteria, and archaea couples electron flow to proton pumping and is adapted to diverse oxygen environments. Remarkably, in mice, neurological disease due to ETC complex I dysfunction is rescued by hypoxia through unknown mechanisms. Here, we show that hypoxia rescue and hyperoxia sensitivity of complex I deficiency are evolutionarily conserved to C. elegans and are specific to mutants that compromise the electron-conducting matrix arm. We show that hypoxia rescue does not involve the hypoxia-inducible factor pathway or attenuation of reactive oxygen species. To discover the mechanism, we use C. elegans genetic screens to identify suppressor mutations in the complex I accessory subunit NDUFA6/nuo-3 that phenocopy hypoxia rescue. We show that NDUFA6/nuo-3(G60D) or hypoxia directly restores complex I forward activity, with downstream rescue of ETC flux and, in some cases, complex I levels. Additional screens identify residues within the ubiquinone binding pocket as being required for the rescue by NDUFA6/nuo-3(G60D) or hypoxia. This reveals oxygen-sensitive coupling between an accessory subunit and the quinone binding pocket of complex I that can restore forward activity in the same manner as hypoxia.
    Keywords:  C. elegans; NADH:ubiquinone oxidoreductase; NDUFA6; NDUFS4; complex I; electron transport chain; hyperoxia; hypoxia; mitochondria; oxygen
    DOI:  https://doi.org/10.1016/j.cell.2023.12.010
  20. Am J Clin Exp Immunol. 2023 ;12(6): 109-126
    The mediating role of inflammaging between mitochondrial dysfunction and sarcopenia in aging: a review.
    Xin Xu, Zixing Wen.
      Sarcopenia, characterized by the insidious reduction of skeletal muscle mass and strength, detrimentally affects the quality of life in elderly cohorts. Present therapeutic strategies are confined to physiotherapeutic interventions, signaling a critical need for elucidation of the etiological underpinnings to facilitate the development of innovative pharmacotherapies. Recent scientific inquiries have associated mitochondrial dysfunction and inflammation with the etiology of sarcopenia. Mitochondria are integral to numerous fundamental cellular processes within muscle tissue, including but not limited to apoptosis, autophagy, signaling via reactive oxygen species, and the maintenance of protein equilibrium. Deviations in mitochondrial dynamics, coupled with compromised oxidative capabilities, autophagic processes, and protein equilibrium, result in disturbances to muscular architecture and functionality. Mitochondrial dysfunction is particularly detrimental as it diminishes oxidative phosphorylation, escalates apoptotic activity, and hinders calcium homeostasis within muscle cells. Additionally, deleterious feedback loops of deteriorated respiration, exacerbated oxidative injury, and diminished quality control mechanisms precipitate the acceleration of muscular senescence. Notably, mitochondria exhibiting deficient energetic metabolism are pivotal in precipitating the shift from normative muscle aging to a pathogenic state. This analytical review meticulously examines the complex interplay between mitochondrial dysfunction, persistent inflammation, and the pathogenesis of sarcopenia. It underscores the imperative to alleviate inflammation and amend mitochondrial anomalies within geriatric populations as a strategy to forestall and manage sarcopenia. An initial overview provides a succinct exposition of sarcopenia and its clinical repercussions. The discourse then progresses to an examination of the direct correlation between mitochondrial dysfunction and the genesis of sarcopenia. Concomitantly, it accentuates potential synergistic effects between inflammatory responses and mitochondrial insufficiencies during the aging of skeletal muscle, thereby casting light upon emergent therapeutic objectives. In culmination, this review distills the prevailing comprehension of the mitochondrial and inflammatory pathways implicated in sarcopenia and delineates extant lacunae in knowledge to orient subsequent scientific inquiry.
    Keywords:  Sarcopenia; inflammaging; mitochondrial dysfunction
  21. Nat Commun. 2024 Jan 09. 15(1): 375
    Upregulated pexophagy limits the capacity of selective autophagy.
    Kyla Germain, Raphaella W L So, Laura F DiGiovanni, Joel C Watts, Robert H J Bandsma, Peter K Kim.
      Selective autophagy is an essential process to maintain cellular homeostasis through the constant recycling of damaged or superfluous components. Over a dozen selective autophagy pathways mediate the degradation of diverse cellular substrates, but whether these pathways can influence one another remains unknown. We address this question using pexophagy, the autophagic degradation of peroxisomes, as a model. We show in cells that upregulated pexophagy impairs the selective autophagy of both mitochondria and protein aggregates by exhausting the autophagy initiation factor, ULK1. We confirm this finding in cell models of the pexophagy-mediated form of Zellweger Spectrum Disorder, a disease characterized by peroxisome dysfunction. Further, we extend the generalizability of limited selective autophagy by determining that increased protein aggregate degradation reciprocally reduces pexophagy using cell models of Parkinson's Disease and Huntington's Disease. Our findings suggest that the degradative capacity of selective autophagy can become limited by an increase in one substrate.
    DOI:  https://doi.org/10.1038/s41467-023-44005-4
  22. EMBO J. 2024 Jan 08.
    Liver ACSM3 deficiency mediates metabolic syndrome via a lauric acid-HNF4α-p38 MAPK axis.
    Xiao Xiao, Ruofei Li, Bing Cui, Cheng Lv, Yu Zhang, Jun Zheng, Rutai Hui, Yibo Wang.
      Metabolic syndrome combines major risk factors for cardiovascular disease, making deeper insight into its pathogenesis important. We here explore the mechanistic basis of metabolic syndrome by recruiting an essential patient cohort and performing extensive gene expression profiling. The mitochondrial fatty acid metabolism enzyme acyl-CoA synthetase medium-chain family member 3 (ACSM3) was identified to be significantly lower expressed in the peripheral blood of metabolic syndrome patients. In line, hepatic ACSM3 expression was decreased in mice with metabolic syndrome. Furthermore, Acsm3 knockout mice showed glucose and lipid metabolic abnormalities, and hepatic accumulation of the ACSM3 fatty acid substrate lauric acid. Acsm3 depletion markedly decreased mitochondrial function and stimulated signaling via the p38 MAPK pathway cascade. Consistently, Acsm3 knockout mouse exhibited abnormal mitochondrial morphology, decreased ATP contents, and enhanced ROS levels in their livers. Mechanistically, Acsm3 deficiency, and lauric acid accumulation activated nuclear receptor Hnf4α-p38 MAPK signaling. In line, the p38 inhibitor Adezmapimod effectively rescued the Acsm3 depletion phenotype. Together, these findings show that disease-associated loss of ACSM3 facilitates mitochondrial dysfunction via a lauric acid-HNF4a-p38 MAPK axis, suggesting a novel therapeutic vulnerability in systemic metabolic dysfunction.
    Keywords:  Acsm3; Lauric Acid; Metabolic Syndrome; Mitochondria Dysfunction; p38 MAPK Signaling Pathway
    DOI:  https://doi.org/10.1038/s44318-023-00020-1
  23. bioRxiv. 2023 Dec 21. pii: 2023.09.07.556674. [Epub ahead of print]
    Unveiling the Intercompartmental Signaling Axis: Mitochondrial to ER Stress Response (MERSR) and its Impact on Proteostasis.
    Jeson J Li, Nan Xin, Chunxia Yang, Larissa A Tavizon, Ruth Hong, Travis I Moore, Rebecca George Tharyan, Adam Antebi, Hyun-Eui Kim.
      Maintaining protein homeostasis is essential for cellular health. During times of proteotoxic stress, cells deploy unique defense mechanisms to achieve resolution. Our previous research uncovered a cross-compartmental Mitochondrial to Cytosolic Stress Response (MCSR), a unique stress response activated by the perturbation of mitochondrial proteostasis, which ultimately results in the improvement of proteostasis in the cytosol. Here, we found that this signaling axis also influences the unfolded protein response of the endoplasmic reticulum (UPR ER ), suggesting the presence of a Mitochondria to ER Stress Response (MERSR). During MERSR, the IRE1 branch of UPR ER is inhibited, introducing a previously unknown regulatory component of MCSR. Moreover, proteostasis is enhanced through the upregulation of the PERK-eIF2a signaling pathway, increasing phosphorylation of eIF2a and improving the ER's capacity to manage greater proteostasis load. MERSR activation in both poly-glutamine (poly-Q) and amyloid-beta (Aβ) C. elegans disease models also led to improvement in both aggregate burden and overall disease outcome. These findings shed light on the coordination between the mitochondria and the ER in maintaining cellular proteostasis and provides further evidence for the importance of intercompartmental signaling.
    DOI:  https://doi.org/10.1101/2023.09.07.556674
  24. J Cell Physiol. 2024 Jan 11.
    Augmented mitochondrial apoptotic signaling impairs C2C12 myoblast differentiation following cellular aging through sequential passaging.
    Fasih A Rahman, Dylan J Hian-Cheong, Kristen Boonstra, Andrew Ma, James P Thoms, Anderson S Zago, Joe Quadrilatero.
      Aging is associated with the steady decline of several cellular processes. The loss of skeletal muscle mass, termed sarcopenia, is one of the major hallmarks of aging. Aged skeletal muscle exhibits a robust reduction in its regenerative capacity due to dysfunction (i.e., senescence, lack of self-renewal, and impaired differentiation) of resident muscle stem cells, called satellite cells. To replicate aging in vitro, immortalized skeletal muscle cells (myoblasts) can be treated with various agents to mimic age-related dysfunction; however, these come with their own set of limitations. In the present study, we used sequential passaging of mouse myoblasts to mimic impaired differentiation that is observed in aged skeletal muscle. Further, we investigated mitochondrial apoptotic mechanisms to better understand the impaired differentiation in these "aged" cells. Our data shows that sequential passaging (>20 passages) of myoblasts is accompanied with significant reductions in differentiation and elevated cell death. Furthermore, high-passage (HP) myoblasts exhibit greater mitochondrial-mediated apoptotic signaling through mitochondrial BAX translocation, CYCS and AIFM1 release, and caspase-9 activation. Finally, we show that inhibition of mitochondrial outer membrane permeability partly recovered differentiation in HP myoblasts. Together, our findings suggests that mitochondrial apoptotic signaling is a contributing factor to the diminished differentiation that is observed in aged myoblasts.
    Keywords:  aging; apoptotic signaling; differentiation; high-passage; mitochondria; skeletal muscle
    DOI:  https://doi.org/10.1002/jcp.31155
  25. bioRxiv. 2023 Dec 23. pii: 2023.12.22.573082. [Epub ahead of print]
    Lipid peroxidation does not mediate muscle atrophy induced by PSD deficiency.
    Hiroaki Eshima, Jordan M Johnson, Katsuhiko Funai.
      Mechanisms by which disuse promotes skeletal muscle atrophy is not well understood. We previously demonstrated that disuse reduces the abundance of mitochondrial phosphatidylethanolamine (PE) in skeletal muscle. Deletion of phosphatidylserine decarboxylase (PSD), an enzyme that generates mitochondrial PE, was sufficient to promote muscle atrophy. In this study, we tested the hypothesis that muscle atrophy induced by PSD deletion is driven by an accumulation of lipid hydroperoxides (LOOH). Mice with muscle-specific knockout of PSD (PSD-MKO) were crossed with glutathione peroxidase 4 (GPx4) transgenic mice (GPx4Tg) to suppress the accumulation of LOOH. However, PSD-MKO × GPx4Tg mice and PSD-MKO mice demonstrated equally robust loss of muscle mass. These results suggest that muscle atrophy induced by PSD deficiency is not driven by the accumulation of LOOH.
    DOI:  https://doi.org/10.1101/2023.12.22.573082
  26. Nat Commun. 2024 Jan 06. 15(1): 347
    High-dimensional phenotyping to define the genetic basis of cellular morphology.
    Matthew Tegtmeyer, Jatin Arora, Samira Asgari, Beth A Cimini, Ajay Nadig, Emily Peirent, Dhara Liyanage, Gregory P Way, Erin Weisbart, Aparna Nathan, Tiffany Amariuta, Kevin Eggan, Marzieh Haghighi, Steven A McCarroll, Luke O'Connor, Anne E Carpenter, Shantanu Singh, Ralda Nehme, Soumya Raychaudhuri.
      The morphology of cells is dynamic and mediated by genetic and environmental factors. Characterizing how genetic variation impacts cell morphology can provide an important link between disease association and cellular function. Here, we combine genomic sequencing and high-content imaging approaches on iPSCs from 297 unique donors to investigate the relationship between genetic variants and cellular morphology to map what we term cell morphological quantitative trait loci (cmQTLs). We identify novel associations between rare protein altering variants in WASF2, TSPAN15, and PRLR with several morphological traits related to cell shape, nucleic granularity, and mitochondrial distribution. Knockdown of these genes by CRISPRi confirms their role in cell morphology. Analysis of common variants yields one significant association and nominate over 300 variants with suggestive evidence (P < 10-6) of association with one or more morphology traits. We then use these data to make predictions about sample size requirements for increasing discovery in cellular genetic studies. We conclude that, similar to molecular phenotypes, morphological profiling can yield insight about the function of genes and variants.
    DOI:  https://doi.org/10.1038/s41467-023-44045-w
  27. bioRxiv. 2023 Dec 22. pii: 2023.12.21.572851. [Epub ahead of print]
    DHCR24-mediated sterol homeostasis during spermatogenesis is required for sperm mitochondrial sheath formation and impacts male fertility over time.
    Sona Relovska, Huafeng Wang, Xinbo Zhang, Pablo Fernández-Tussy, Kyung Jo Jeong, Jungmin Choi, Yajaira Suárez, Jeffrey G McDonald, Carlos Fernández-Hernando, Jean-Ju Chung.
      Desmosterol and cholesterol are essential lipid components of the sperm plasma membrane. Cholesterol efflux is required for capacitation, a process through which sperm acquire fertilizing ability. In this study, using a transgenic mouse model overexpressing 24-dehydrocholesterol reductase (DHCR24), an enzyme in the sterol biosynthesis pathway responsible for the conversion of desmosterol to cholesterol, we show that disruption of sterol homeostasis during spermatogenesis led to defective sperm morphology characterized by incomplete mitochondrial packing in the midpiece, reduced sperm count and motility, and a decline in male fertility with increasing paternal age, without changes in body fat composition. Sperm depleted of desmosterol exhibit inefficiency in the acrosome reaction, metabolic dysfunction, and an inability to fertilize the egg. These findings provide molecular insights into sterol homeostasis for sperm capacitation and its impact on male fertility.
    Keywords:  24-dehydrocholesterol reductase; cellular metabolism; cholesterol; male infertility; mitochondrial packing; spermatozoa; sterol homeostasis
    DOI:  https://doi.org/10.1101/2023.12.21.572851
  28. bioRxiv. 2023 Dec 18. pii: 2023.12.17.572088. [Epub ahead of print]
    Effects of aging on glucose and lipid metabolism in mice.
    Evan C Lien, Ngoc Vu, Anna M Westermark, Laura V Danai, Allison N Lau, Yetiş Gültekin, Matthew A Kukurugya, Bryson D Bennett, Matthew G Vander Heiden.
      Aging is accompanied by multiple molecular changes that contribute to aging-associated pathologies, such as accumulation of cellular damage and mitochondrial dysfunction. Tissue metabolism can also change with age, in part because mitochondria are central to cellular metabolism. Moreover, the co-factor NAD+, which is reported to decline across multiple tissue types during aging, plays a central role in metabolic pathways such as glycolysis, the tricarboxylic acid cycle, and the oxidative synthesis of nucleotides, amino acids, and lipids. To further characterize how tissue metabolism changes with age, we intravenously infused [U-13C]-glucose into young and old C57BL/6J, WSB/EiJ, and Diversity Outbred mice to trace glucose fate into downstream metabolites within plasma, liver, gastrocnemius muscle, and brain tissues. We found that glucose incorporation into central carbon and amino acid metabolism was robust during healthy aging across these different strains of mice. We also observed that levels of NAD+, NADH, and the NAD+/NADH ratio were unchanged in these tissues with healthy aging. However, aging tissues, particularly brain, exhibited evidence of up-regulated fatty acid and sphingolipid metabolism reactions that regenerate NAD+ from NADH. Because mitochondrial respiration, a major source of NAD+ regeneration, is reported to decline with age, our data supports a model where NAD+-generating lipid metabolism reactions may buffer against changes in NAD+/NADH during healthy aging.
    DOI:  https://doi.org/10.1101/2023.12.17.572088
  29. Int J Mol Sci. 2023 Dec 21. pii: 124. [Epub ahead of print]25(1):
    Molecular Mechanisms of Neuroprotection by Ketone Bodies and Ketogenic Diet in Cerebral Ischemia and Neurodegenerative Diseases.
    Jiwon Jang, Su Rim Kim, Jo Eun Lee, Seoyeon Lee, Hyeong Jig Son, Wonchae Choe, Kyung-Sik Yoon, Sung Soo Kim, Eui-Ju Yeo, Insug Kang.
      Ketone bodies (KBs), such as acetoacetate and β-hydroxybutyrate, serve as crucial alternative energy sources during glucose deficiency. KBs, generated through ketogenesis in the liver, are metabolized into acetyl-CoA in extrahepatic tissues, entering the tricarboxylic acid cycle and electron transport chain for ATP production. Reduced glucose metabolism and mitochondrial dysfunction correlate with increased neuronal death and brain damage during cerebral ischemia and neurodegeneration. Both KBs and the ketogenic diet (KD) demonstrate neuroprotective effects by orchestrating various cellular processes through metabolic and signaling functions. They enhance mitochondrial function, mitigate oxidative stress and apoptosis, and regulate epigenetic and post-translational modifications of histones and non-histone proteins. Additionally, KBs and KD contribute to reducing neuroinflammation and modulating autophagy, neurotransmission systems, and gut microbiome. This review aims to explore the current understanding of the molecular mechanisms underpinning the neuroprotective effects of KBs and KD against brain damage in cerebral ischemia and neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease.
    Keywords:  Alzheimer’s disease; Parkinson’s disease; cerebral ischemia; ketogenic diet; ketone bodies; mitochondrial dysfunction; neurodegenerative disease; neuroinflammation; oxidative stress; β-hydroxybutyrate
    DOI:  https://doi.org/10.3390/ijms25010124
  30. Res Sq. 2023 Dec 21. pii: rs.3.rs-3755231. [Epub ahead of print]
    Sulfur Amino Acid Restriction alters mitochondrial function depending on tissue, sex, and Methionine sulfoxide reductase A (MsrA) status.
    Kevin M Thyne, Raechel Camones, Adam B Salmon.
      Methionine restriction (MR) has been shown to affect mitochondrial function including altering oxygen consumption, reactive oxygen species (ROS) generation, Complex expression, and oxidative damage. The sulfur-containing amino acid methionine can become oxidized forming methionine sulfoxide which can lead to changes in protein function and signaling. Methionine sulfoxide reductases are endogenous enzymes capable of reducing methionine sulfoxide, with Methionine sulfoxide reductase A (MsrA) being ubiquitously expressed in mammals. Here we investigated if the effects of MR on mitochondrial function required functional MsrA in the liver and kidney which are the major tissues involved in sulfur biochemistry and both highly express MsrA. Moreover, MsrA is endogenously found in the mitochondria thereby providing potential mechanisms linking diet to mitochondrial phenotype. We found sex-specific changes in oxygen consumption of isolated mitochondria and females showed changes with MR in a tissue-dependent manner - increased in liver and decreased in kidney. Loss of MsrA increased or decreased oxygen consumption depending on the tissue and which portion of the electron transport chain was being tested. In general, males had few changes in either tissue regardless of MR or MsrA status. Hydrogen peroxide production was increased in the kidney with MR regardless of sex or MsrA status. However, in the liver, production was increased by MR in females and only slightly higher with loss of MsrA in both sexes. Mitochondrial Complex expression was found to be largely unchanged in either tissue suggesting these effects are driven by regulatory mechanisms and not by changes in expression. Together these results suggest that sex and MsrA status do impact the mitochondrial effects of MR in a tissue-specific manner.
    DOI:  https://doi.org/10.21203/rs.3.rs-3755231/v1
  31. bioRxiv. 2023 Dec 22. pii: 2023.12.21.572870. [Epub ahead of print]
    Human telomere length is chromosome specific and conserved across individuals.
    Kayarash Karimian, Aljona Groot, Vienna Huso, Ramin Kahidi, Kar-Tong Tan, Samantha Sholes, Rebecca Keener, John F McDyer, Jonathan K Alder, Heng Li, Andreas Rechtsteiner, Carol W Greider.
      Short telomeres cause age-related disease and long telomeres predispose to cancer; however, the mechanisms regulating telomere length are unclear. Current methods for telomere length measurement are not direct, precise, or widely accessible. Here we describe a direct nanopore telomere profiling assay using an Oxford Nanopore Technology (ONT) MinION that is easy to implement, precise, and cost effective with broad applications in research, and the clinic. Telomere length measurement is currently used in clinical settings to make highly consequential treatment decisions. Using patient samples our method returned similar results to the clinical, FlowFISH assay. Telomere profiling enables mapping of the telomere to specific chromosomes, and we identified both chromosome-specific and haplotype-specific telomere length distribution with a remarkable 6kb difference between some telomere lengths. Further, we found that specific chromosome ends were consistently shorter or longer than the average length across 150 individuals. The presence of conserved chromosome end-specific telomere lengths suggests there are new paradigms in telomere biology that are yet to be explored. Understanding these mechanisms will allow deeper insights into telomere biology that can lead to new approaches to disease.
    DOI:  https://doi.org/10.1101/2023.12.21.572870
  32. Cells. 2023 Dec 20. pii: 12. [Epub ahead of print]13(1):
    Mitochondrial Targeting against Alzheimer's Disease: Lessons from Hibernation.
    Christina F de Veij Mestdagh, August B Smit, Robert H Henning, Ronald E van Kesteren.
      Alzheimer's disease (AD) is the most common cause of dementia worldwide and yet remains without effective therapy. Amongst the many proposed causes of AD, the mitochondrial cascade hypothesis is gaining attention. Accumulating evidence shows that mitochondrial dysfunction is a driving force behind synaptic dysfunction and cognitive decline in AD patients. However, therapies targeting the mitochondria in AD have proven unsuccessful so far, and out-of-the-box options, such as hibernation-derived mitochondrial mechanisms, may provide valuable new insights. Hibernators uniquely and rapidly alternate between suppression and re-activation of the mitochondria while maintaining a sufficient energy supply and without acquiring ROS damage. Here, we briefly give an overview of mitochondrial dysfunction in AD, how it affects synaptic function, and why mitochondrial targeting in AD has remained unsuccessful so far. We then discuss mitochondria in hibernation and daily torpor in mice, covering current advancements in hibernation-derived mitochondrial targeting strategies. We conclude with new ideas on how hibernation-derived dual mitochondrial targeting of both the ATP and ROS pathways may boost mitochondrial health and induce local synaptic protein translation to increase synaptic function and plasticity. Further exploration of these mechanisms may provide more effective treatment options for AD in the future.
    Keywords:  Alzheimer’s disease; SUL-138; daily torpor; hibernation-derived compound; mitochondrial dysfunction
    DOI:  https://doi.org/10.3390/cells13010012
  33. Vet Microbiol. 2023 Dec 30. pii: S0378-1135(23)00327-9. [Epub ahead of print]290 109973
    NDV inhibited IFN-β secretion through impeding CHCHD10-mediated mitochondrial fusion to promote viral proliferation.
    Xibing Yu, Hexiang Jiang, Jindou Li, Jiaxin Ding, Kainan Chen, Zhuang Ding, Xiaohong Xu.
      Newcastle disease virus (NDV) is an RNA virus that can promote its own replication through the inhibition of cellular mitochondrial fusion. The proteins involved in mitochondrial fusion, namely mitofusin 1 (Mfn1) and optic atrophy 1 (OPA1) are associated with interferon-beta (IFN-β) secretion during NDV infection. However, the precise mechanism by which NDV modulates the Mfn1-mediated or OPA1-mediated fusion of mitochondria, thereby impacting IFN-β, remains elusive. This study revealed that the downregulation of the mitochondrial protein known as coiled-coil-helix-coiled-coil-helix domain containing 10 (CHCHD10) exerts a negative regulatory effect on OPA1 and Mfn1 in human lung adenocarcinoma (A549) cells during the late stage of NDV infection. This reduction in CHCHD10 expression impeded cellular mitochondrial fusion, subsequently leading to a decline in the activation of interferon regulatory factor 3 (IRF3) and nuclear factor kappa B (NF-κB), ultimately resulting in diminished secretion of IFN-β. In contrast, the overexpression of CHCHD10 alleviated infection-induced detrimental effect in mitochondrial fusion, thereby impeding viral proliferation. In summary, NDV enhances its replication by inhibiting the CHCHD10 protein, which impedes mitochondrial fusion and suppresses IFN-β production through the activation of IRF3 and NF-κB.
    Keywords:  CHCHD10; IFN-β; IRF3; Mitochondrial fusion; NDV; NF-κB
    DOI:  https://doi.org/10.1016/j.vetmic.2023.109973
  34. iScience. 2024 Jan 19. 27(1): 108700
    Developmental changes of the mitochondria in the murine anteroventral cochlear nucleus.
    Anika Hintze, Felix Lange, Anna M Steyer, Jannis Anstatt, Wiebke Möbius, Stefan Jakobs, Carolin Wichmann.
      Mitochondria are key organelles to provide ATP for synaptic transmission. This study aims to unravel the structural adaptation of mitochondria to an increase in presynaptic energy demand and upon the functional impairment of the auditory system. We use the anteroventral cochlear nucleus (AVCN) of wild-type and congenital deaf mice before and after hearing onset as a model system for presynaptic states of lower and higher energy demands. We combine focused ion beam scanning electron microscopy and electron tomography to investigate mitochondrial morphology. We found a larger volume of synaptic boutons and mitochondria after hearing onset with a higher crista membrane density. In deaf animals lacking otoferlin, we observed a shallow increase of mitochondrial volumes toward adulthood in endbulbs, while in wild-type animals mitochondria further enlarged. We propose that in the AVCN, presynaptic mitochondria undergo major structural changes likely to serve higher energy demands upon the onset of hearing and further maturation.
    Keywords:  Cell biology; Developmental biology
    DOI:  https://doi.org/10.1016/j.isci.2023.108700
  35. medRxiv. 2023 Dec 20. pii: 2023.12.20.23300170. [Epub ahead of print]
    Loss of Function of the Cytoplasmic Fe-S Assembly Protein CIAO1 Causes a Neuromuscular Disorder with Compromise of Nucleocytoplasmic Fe-S Enzymes.
    Nunziata Maio, Rotem Orbach, Irina Zaharieva, Ana Töpf, Sandra Donkervoort, Pinki Munot, Juliane Mueller, Tracey Willis, Sumit Verma, Stojan Peric, Deepa Krishnakumar, Sniya Sudhakar, Aileen Reghan Foley, Sarah Silverstein, Ganka Douglas, Lynn Pais, Stephanie DiTroia, Christopher Grunseich, Ying Hu, Caroline Sewry, Anna Sarkozy, Volker Straub, Francesco Muntoni, Tracey Rouault, Carsten Gerhart Bönnemann.
      Cytoplasmic and nuclear iron-sulfur enzymes that are essential for genome maintenance and replication depend on the cytoplasmic iron-sulfur assembly (CIA) machinery for cluster acquisition. Here we report that patients with biallelic loss of function in CIAO1 , a key CIA component, develop proximal and axial muscle weakness, fluctuating creatine kinase elevation and respiratory insufficiency. In addition, they present with CNS symptoms including learning difficulties and neurobehavioral comorbidities, along with iron deposition in deep brain nuclei, macrocytic anemia and gastrointestinal symptoms. Mutational analysis and functional assays revealed reduced stability of the variants compared to wild-type CIAO1. Loss of CIAO1 impaired DNA helicases, polymerases and repair enzymes which rely on the CIA complex to acquire their Fe-S cofactors, with lentiviral restoration reversing all patient-derived cellular abnormalities. Our study identifies CIAO1 as a novel human disease gene and provides insights into the broader implications of the iron-sulfur assembly pathway in human health and disease.
    DOI:  https://doi.org/10.1101/2023.12.20.23300170
  36. Proc Natl Acad Sci U S A. 2024 Jan 16. 121(3): e2307904121
    Systems-level analyses dissociate genetic regulators of reactive oxygen species and energy production.
    Neal K Bennett, Megan Lee, Adam L Orr, Ken Nakamura.
      Respiratory chain dysfunction can decrease ATP and increase reactive oxygen species (ROS) levels. Despite the importance of these metabolic parameters to a wide range of cellular functions and disease, we lack an integrated understanding of how they are differentially regulated. To address this question, we adapted a CRISPRi- and FACS-based platform to compare the effects of respiratory gene knockdown on ROS to their effects on ATP. Focusing on genes whose knockdown is known to decrease mitochondria-derived ATP, we showed that knockdown of genes in specific respiratory chain complexes (I, III, and CoQ10 biosynthesis) increased ROS, whereas knockdown of other low ATP hits either had no impact (mitochondrial ribosomal proteins) or actually decreased ROS (complex IV). Moreover, although shifting metabolic conditions profoundly altered mitochondria-derived ATP levels, it had little impact on mitochondrial or cytosolic ROS. In addition, knockdown of a subset of complex I subunits-including NDUFA8, NDUFB4, and NDUFS8-decreased complex I activity, mitochondria-derived ATP, and supercomplex level, but knockdown of these genes had differential effects on ROS. Conversely, we found an essential role for ether lipids in the dynamic regulation of mitochondrial ROS levels independent of ATP. Thus, our results identify specific metabolic regulators of cellular ATP and ROS balance that may help dissect the roles of these processes in disease and identify therapeutic strategies to independently target energy failure and oxidative stress.
    Keywords:  ATP; CRISPRi; ROS; metabolism; mitochondria
    DOI:  https://doi.org/10.1073/pnas.2307904121
  37. Eur J Med Genet. 2024 Jan 08. pii: S1769-7212(24)00001-6. [Epub ahead of print] 104909
    Evaluating ClinGen variant curation expert panels' application of PVS1 code.
    Xiaoyan Wang, Haibo Li, Haiyan Luo, Yongyi Zou, Haoxian Li, Yayun Qin, Jieping Song.
       BACKGROUND: The 2015 American College of Medical Genetics and Genomics (ACMG) and Association for Molecular Pathology (AMP) guidelines articulates that the effects of certain types of variants on gene function can often be seen as a complete absence of the gene product by leading to a lack of transcription or nonsense-mediated decay(NMD). However, detailed information considering different types of loss of function(LOF) variants, refined steps assimilating details concerning location of variant, changes in strength levels, NMD boundary, or any additional information pointing to a true null effect, were all left to expert judgement. As part of its Clinical Genome Resource (ClinGen) initiative, Variant Curation Expert Panels (VCEPs) are designated to make gene/disease-centric specifications in accordance with the ACMG/AMP guidelines, including a more detailed definition of what constitutes an appropriate LOF evidence. Our goal was to evaluate the current LOF guidelines developed by the VCEPs and analyse the prior curated variants concerning the PVS1 criteria, bringing people occupied in genetic data analysis a comprehensive understanding of this code.
    METHODS: Our study evaluated 7 VCEPs for their LOF criteria (PVS1). Subsequently, we assessed the predictive criteria by considering the underlying disease mechanism, protein transcript, and variant types delineated. Then, we meticulously curated the LOF evidence referenced by each VCEP in their preliminary variant classification, thereby scrutinizing the recommendations put forth by VCEPs and their application in the interpretation of the aforementioned predictive criteria. Based on these, an extensive curation of evidence summary considering PVS1 applied by VCEPs according to their classification of pilot variants for the purpose of analyzing VCEP criteria specifications and their use in the understanding of LOF was conducted.
    RESULTS: We observed in this article that the VCEPs discussed followed the majority of Sequence Variant Interpretation (SVI) recommendations concerning the application of this LOF criteria, except for some disease/gene specific considerations. We highlighted the wide range of PVS1 strength levels approved by VCEP, reflecting the diversity of evidence for each variants type. In addition, we observed substantial differences in the approach used to determine relative strengths for different types of null variants and in the attitude towards these principles concerning variant location, NMD and influence to protein function between VCEPs.
    CONCLUSIONS: It is difficult to understand the intricacies of the predictive data(PVS1), which often requires expert-level knowledge of disease/gene. The VCEP criteria specifications for the predictive evidence play an important role in making it more accessible for the curators to apply the predictive data by providing details concerning this complex criteria. Despite this, we believe there is a need for more guidance on standardizing this process and ensuring consistency in the application of this predictive evidence.
    Keywords:  ACMG/AMP; Classification; PVS1; VCEP; Variants
    DOI:  https://doi.org/10.1016/j.ejmg.2024.104909
  38. bioRxiv. 2023 Dec 23. pii: 2023.12.23.573206. [Epub ahead of print]
    Exogenous mitochondrial transfer increases energy expenditure and attenuates adiposity gains in mice with diet-induced obesity.
    Maria Namwanje, Soumi Mazumdar, Amanda Stayton, Prisha S Patel, Christine Watkins, Catrina White, Chester Brown, James D Eason, Khyobeni Mozhui, Cem Kuscu, Navjot Pabla, Erin J Stephenson, Amandeep Bajwa.
      Obesity is associated with chronic multi-system bioenergetic stress that may be improved by increasing the number of healthy mitochondria available across organ systems. However, treatments capable of increasing mitochondrial content are generally limited to endurance exercise training paradigms, which are not always sustainable long-term, let alone feasible for many patients with obesity. Recent studies have shown that local transfer of exogenous mitochondria from healthy donor tissues can improve bioenergetic outcomes and alleviate the effects of tissue injury in recipients with organ specific disease. Thus, the aim of this project was to determine the feasibility of systemic mitochondrial transfer for improving energy balance regulation in the setting of diet-induced obesity. We found that transplantation of mitochondria from lean mice into mice with diet-induced obesity attenuated adiposity gains by increasing energy expenditure and promoting the mobilization and oxidation of lipids. Additionally, mice that received exogenous mitochondria demonstrated improved glucose uptake, greater insulin responsiveness, and complete reversal of hepatic steatosis. These changes were, in part, driven by adaptations occurring in white adipose tissue. Together, these findings are proof-of-principle that mitochondrial transplantation is an effective therapeutic strategy for limiting the deleterious metabolic effects of diet-induced obesity in mice.
    DOI:  https://doi.org/10.1101/2023.12.23.573206
  39. J Inflamm (Lond). 2024 Jan 11. 21(1): 1
    Interleukin-6-elicited chronic neuroinflammation may decrease survival but is not sufficient to drive disease progression in a mouse model of Leigh syndrome.
    Kevin Aguilar, Carla Canal, Gemma Comes, Sandra Díaz-Clavero, Maria Angeles Llanos, Albert Quintana, Elisenda Sanz, Juan Hidalgo.
       BACKGROUND: Mitochondrial diseases (MDs) are genetic disorders characterized by dysfunctions in mitochondria. Clinical data suggest that additional factors, beyond genetics, contribute to the onset and progression of this group of diseases, but these influencing factors remain largely unknown. Mounting evidence indicates that immune dysregulation or distress could play a role. Clinical observations have described the co-incidence of infection and the onset of the disease as well as the worsening of symptoms following infection. These findings highlight the complex interactions between MDs and immunity and underscore the need to better understand their underlying relationships.
    RESULTS: We used Ndufs4 KO mice, a well-established mouse model of Leigh syndrome (one of the most relevant MDs), to test whether chronic induction of a neuroinflammatory state in the central nervous system before the development of neurological symptoms would affect both the onset and progression of the disease in Ndufs4 KO mice. To this aim, we took advantage of the GFAP-IL6 mouse, which overexpresses interleukin-6 (IL-6) in astrocytes and produces chronic glial reactivity, by generating a mouse line with IL-6 overexpression and NDUFS4 deficiency. IL-6 overexpression aggravated the mortality of female Ndufs4 KO mice but did not alter the main motor and respiratory phenotypes measured in any sex. Interestingly, an abnormal region-dependent microglial response to IL-6 overexpression was observed in Ndufs4 KO mice compared to controls.
    CONCLUSION: Overall, our data indicate that chronic neuroinflammation may worsen the disease in Ndufs4 KO female mice, but not in males, and uncovers an abnormal microglial response due to OXPHOS dysfunction, which may have implications for our understanding of the effect of OXPHOS dysfunction in microglia.
    Keywords:  Astrocytes; GFAP-IL6; IL-6; Leigh syndrome; Microglia; Ndufs4 KO; Neuroinflammation
    DOI:  https://doi.org/10.1186/s12950-023-00369-4
  40. Methods. 2024 Jan 05. pii: S1046-2023(23)00218-9. [Epub ahead of print]
    Microbiome metabolite quantification methods enabling insights into human health and disease.
    Jarrod Roach, Rohit Mital, Jacob J Haffner, Nathan Colwell, Randy Coats, Horvey M Palacios, Zongyuan Liu, Joseane L P Godinho, Monica Ness, Thilini Peramuna, Laura-Isobel McCall.
      Many of the health-associated impacts of the microbiome are mediated by its chemical activity, producing and modifying small molecules (metabolites). Thus, microbiome metabolite quantification has a central role in efforts to elucidate and measure microbiome function. In this review, we cover general considerations when designing experiments to quantify microbiome metabolites, including sample preparation, data acquisition and data processing, since these are critical to downstream data quality. We then discuss data analysis and experimental steps to demonstrate that a given metabolite feature is of microbial origin. We further discuss techniques used to quantify common microbial metabolites, including short-chain fatty acids (SCFA), secondary bile acids (BAs), tryptophan derivatives, N-acyl amides and trimethylamine N-oxide (TMAO). Lastly, we conclude with challenges and future directions for the field.
    Keywords:  Bile acids; Data processing; Instrumental methods; Mass spectrometry; Microbiome metabolite quantification; Short-chain fatty acids
    DOI:  https://doi.org/10.1016/j.ymeth.2023.12.007
  41. medRxiv. 2023 Dec 21. pii: 2023.12.20.23300294. [Epub ahead of print]
    Rare disease gene association discovery from burden analysis of the 100,000 Genomes Project data.
    Valentina Cipriani, Letizia Vestito, Emma F Magavern, Julius Ob Jacobsen, Gavin Arno, Elijah R Behr, Katherine A Benson, Marta Bertoli, Detlef Bockenhauer, Michael R Bowl, Kate Burley, Li F Chan, Patrick Chinnery, Peter Conlon, Marcos Costa, Alice E Davidson, Sally J Dawson, Elhussein Elhassan, Sarah E Flanagan, Marta Futema, Daniel P Gale, Sonia García-Ruiz, Cecilia Gonzalez Corcia, Helen R Griffin, Sophie Hambleton, Amy R Hicks, Henry Houlden, Richard S Houlston, Sarah A Howles, Robert Kleta, Iris Lekkerkerker, Siying Lin, Petra Liskova, Hannah Mitchison, Heba Morsy, Andrew D Mumford, William G Newman, Ruxandra Neatu, Edel A O'Toole, Albert Cm Ong, Alistair T Pagnamenta, Shamima Rahman, Neil Rajan, Peter N Robinson, Mina Ryten, Omid Sadeghi-Alavijeh, John A Sayer, Claire L Shovlin, Jenny C Taylor, Omri Teltsh, Ian Tomlinson, Arianna Tucci, Clare Turnbull, Albertien M van Eerde, James S Ware, Laura M Watts, Andrew R Webster, Sarah K Westbury, Sean L Zheng, Mark Caulfield, Damian Smedley.
      To discover rare disease-gene associations, we developed a gene burden analytical framework and applied it to rare, protein-coding variants from whole genome sequencing of 35,008 cases with rare diseases and their family members recruited to the 100,000 Genomes Project (100KGP). Following in silico triaging of the results, 88 novel associations were identified including 38 with existing experimental evidence. We have published the confirmation of one of these associations, hereditary ataxia with UCHL1 , and independent confirmatory evidence has recently been published for four more. We highlight a further seven compelling associations: hypertrophic cardiomyopathy with DYSF and SLC4A3 where both genes show high/specific heart expression and existing associations to skeletal dystrophies or short QT syndrome respectively; monogenic diabetes with UNC13A with a known role in the regulation of β cells and a mouse model with impaired glucose tolerance; epilepsy with KCNQ1 where a mouse model shows seizures and the existing long QT syndrome association may be linked; early onset Parkinson's disease with RYR1 with existing links to tremor pathophysiology and a mouse model with neurological phenotypes; anterior segment ocular abnormalities associated with POMK showing expression in corneal cells and with a zebrafish model with developmental ocular abnormalities; and cystic kidney disease with COL4A3 showing high renal expression and prior evidence for a digenic or modifying role in renal disease. Confirmation of all 88 associations would lead to potential diagnoses in 456 molecularly undiagnosed cases within the 100KGP, as well as other rare disease patients worldwide, highlighting the clinical impact of a large-scale statistical approach to rare disease gene discovery.
    DOI:  https://doi.org/10.1101/2023.12.20.23300294
  42. Cell Mol Life Sci. 2024 Jan 12. 81(1): 34
    Contributing roles of mitochondrial dysfunction and hepatocyte apoptosis in liver diseases through oxidative stress, post-translational modifications, inflammation, and intestinal barrier dysfunction.
    Karli R LeFort, Wiramon Rungratanawanich, Byoung-Joon Song.
      This review provides an update on recent findings from basic, translational, and clinical studies on the molecular mechanisms of mitochondrial dysfunction and apoptosis of hepatocytes in multiple liver diseases, including but not limited to alcohol-associated liver disease (ALD), metabolic dysfunction-associated steatotic liver disease (MASLD), and drug-induced liver injury (DILI). While the ethanol-inducible cytochrome P450-2E1 (CYP2E1) is mainly responsible for oxidizing binge alcohol via the microsomal ethanol oxidizing system, it is also responsible for metabolizing many xenobiotics, including pollutants, chemicals, drugs, and specific diets abundant in n-6 fatty acids, into toxic metabolites in many organs, including the liver, causing pathological insults through organelles such as mitochondria and endoplasmic reticula. Oxidative imbalances (oxidative stress) in mitochondria promote the covalent modifications of lipids, proteins, and nucleic acids through enzymatic and non-enzymatic mechanisms. Excessive changes stimulate various post-translational modifications (PTMs) of mitochondrial proteins, transcription factors, and histones. Increased PTMs of mitochondrial proteins inactivate many enzymes involved in the reduction of oxidative species, fatty acid metabolism, and mitophagy pathways, leading to mitochondrial dysfunction, energy depletion, and apoptosis. Unique from other organelles, mitochondria control many signaling cascades involved in bioenergetics (fat metabolism), inflammation, and apoptosis/necrosis of hepatocytes. When mitochondrial homeostasis is shifted, these pathways become altered or shut down, likely contributing to the death of hepatocytes with activation of inflammation and hepatic stellate cells, causing liver fibrosis and cirrhosis. This review will encapsulate how mitochondrial dysfunction contributes to hepatocyte apoptosis in several types of liver diseases in order to provide recommendations for targeted therapeutics.
    Keywords:  ALDH2; Alcohol-associated liver disease; Apoptosis; CYP2E1; Drug-induced liver injury; Endotoxemia; Gut–liver axis; Intestinal barrier dysfunction; Metabolic dysfunction-associated steatotic liver disease; Microbiota; Mitochondrial dysfunction; Oxidative stress; Post-translational modifications; Viral hepatitis
    DOI:  https://doi.org/10.1007/s00018-023-05061-7
  43. Nat Chem Biol. 2024 Jan 11.
    Ironing out the mitochondria.
    Junsheng Chen, Tadashi Makio, Thomas Simmen.
      
    DOI:  https://doi.org/10.1038/s41589-023-01509-w
  44. Genome Med. 2024 Jan 08. 16(1): 3
    MAGPIE: accurate pathogenic prediction for multiple variant types using machine learning approach.
    Yicheng Liu, Tianyun Zhang, Ningyuan You, Sai Wu, Ning Shen.
      Identifying pathogenic variants from the vast majority of nucleotide variation remains a challenge. We present a method named Multimodal Annotation Generated Pathogenic Impact Evaluator (MAGPIE) that predicts the pathogenicity of multi-type variants. MAGPIE uses the ClinVar dataset for training and demonstrates superior performance in both the independent test set and multiple orthogonal validation datasets, accurately predicting variant pathogenicity. Notably, MAGPIE performs best in predicting the pathogenicity of rare variants and highly imbalanced datasets. Overall, results underline the robustness of MAGPIE as a valuable tool for predicting pathogenicity in various types of human genome variations. MAGPIE is available at https://github.com/shenlab-genomics/magpie .
    Keywords:  Genomic variation; Machine learning; Multimodal annotation; Pathogenic prediction
    DOI:  https://doi.org/10.1186/s13073-023-01274-4
  45. J Genet Genomics. 2024 Jan 04. pii: S1673-8527(24)00001-8. [Epub ahead of print]
    CircPTEN-MT from PTEN regulates mitochondrial energy metabolism.
    Danhui Ruan, Jiancheng Xu, Yang Liu, Juan Luo, Xuyang Zhao, Yuhua Li, Guangxi Wang, Jiawen Feng, Hui Liang, Yue Yin, Jianyuan Luo, Yuxin Yin.
      PTEN is a multifunctional gene that is involved in a variety of physiological and pathological processes. Circular RNAs (circRNAs) are generated from back-splicing events during mRNA processing and participate in cell biological processes through binding to RNAs or proteins. However, PTEN-related circRNAs are largely unknown. Here we report that circPTEN-MT (hsa_circ_0002934) is a circular RNA encoded by exons 3, 4, and 5 of PTEN and is a critical regulator of mitochondrial energy metabolism. CircPTEN-MT is localized to mitochondria and physically associated with leucine-rich pentatricopeptide repeat-containing protein (LRPPRC), which regulates posttranscriptional gene expression in mitochondria. Knocking down circPTEN-MT reduces the interaction of LRPPRC and SRA stem-loop interacting RNA binding protein (SLIRP) and inhibits the polyadenylation of mitochondrial mRNA, which decreases the mRNA level of the mitochondrial complex Ι subunit and reduces mitochondrial membrane potential (MMP) and ATP production. Our data demonstrate that circPTEN-MT is an important regulator of cellular energy metabolism. This study expands our understanding of the role of PTEN which produces both linear and circular RNAs with different and independent functions.
    Keywords:  Circular RNA/ LRPPRC/ Mitochondrial energy metabolism/ mtDNA post-transcriptional regulation
    DOI:  https://doi.org/10.1016/j.jgg.2023.12.011
  46. J Gen Physiol. 2024 Feb 05. pii: e202313451. [Epub ahead of print]156(2):
    Electro-metabolic signaling.
    Thomas A Longden, W Jonathan Lederer.
      Precise matching of energy substrate delivery to local metabolic needs is essential for the health and function of all tissues. Here, we outline a mechanistic framework for understanding this critical process, which we refer to as electro-metabolic signaling (EMS). All tissues exhibit changes in metabolism over varying spatiotemporal scales and have widely varying energetic needs and reserves. We propose that across tissues, common signatures of elevated metabolism or increases in energy substrate usage that exceed key local thresholds rapidly engage mechanisms that generate hyperpolarizing electrical signals in capillaries that then relax contractile elements throughout the vasculature to quickly adjust blood flow to meet changing needs. The attendant increase in energy substrate delivery serves to meet local metabolic requirements and thus avoids a mismatch in supply and demand and prevents metabolic stress. We discuss in detail key examples of EMS that our laboratories have discovered in the brain and the heart, and we outline potential further EMS mechanisms operating in tissues such as skeletal muscle, pancreas, and kidney. We suggest that the energy imbalance evoked by EMS uncoupling may be central to cellular dysfunction from which the hallmarks of aging and metabolic diseases emerge and may lead to generalized organ failure states-such as diverse flavors of heart failure and dementia. Understanding and manipulating EMS may be key to preventing or reversing these dysfunctions.
    DOI:  https://doi.org/10.1085/jgp.202313451
  47. BMC Pediatr. 2024 Jan 13. 24(1): 37
    Assessing the quality and value of metabolic chart data for capturing core outcomes for pediatric medium-chain acyl-CoA dehydrogenase (MCAD) deficiency.
    Ryan Iverson, Monica Taljaard, Michael T Geraghty, Michael Pugliese, Kylie Tingley, Doug Coyle, Jonathan B Kronick, Kumanan Wilson, Valerie Austin, Catherine Brunel-Guitton, Daniela Buhas, Nancy J Butcher, Alicia K J Chan, Sarah Dyack, Sharan Goobie, Cheryl R Greenberg, Shailly Jain-Ghai, Michal Inbar-Feigenberg, Natalya Karp, Mariya Kozenko, Erica Langley, Matthew Lines, Julian Little, Jennifer MacKenzie, Bruno Maranda, Saadet Mercimek-Andrews, Aizeddin Mhanni, John J Mitchell, Laura Nagy, Martin Offringa, Amy Pender, Murray Potter, Chitra Prasad, Suzanne Ratko, Ramona Salvarinova, Andreas Schulze, Komudi Siriwardena, Neal Sondheimer, Rebecca Sparkes, Sylvia Stockler-Ipsiroglu, Kendra Tapscott, Yannis Trakadis, Lesley Turner, Clara Van Karnebeek, Anthony Vandersteen, Jagdeep S Walia, Brenda J Wilson, Andrea C Yu, Beth K Potter, Pranesh Chakraborty.
       BACKGROUND: Generating rigorous evidence to inform care for rare diseases requires reliable, sustainable, and longitudinal measurement of priority outcomes. Having developed a core outcome set for pediatric medium-chain acyl-CoA dehydrogenase (MCAD) deficiency, we aimed to assess the feasibility of prospective measurement of these core outcomes during routine metabolic clinic visits.
    METHODS: We used existing cohort data abstracted from charts of 124 children diagnosed with MCAD deficiency who participated in a Canadian study which collected data from birth to a maximum of 11 years of age to investigate the frequency of clinic visits and quality of metabolic chart data for selected outcomes. We recorded all opportunities to collect outcomes from the medical chart as a function of visit rate to the metabolic clinic, by treatment centre and by child age. We applied a data quality framework to evaluate data based on completeness, conformance, and plausibility for four core MCAD outcomes: emergency department use, fasting time, metabolic decompensation, and death.
    RESULTS: The frequency of metabolic clinic visits decreased with increasing age, from a rate of 2.8 visits per child per year (95% confidence interval, 2.3-3.3) among infants 2 to 6 months, to 1.0 visit per child per year (95% confidence interval, 0.9-1.2) among those ≥ 5 years of age. Rates of emergency department visits followed anticipated trends by child age. Supplemental findings suggested that some emergency visits occur outside of the metabolic care treatment centre but are not captured. Recommended fasting times were updated relatively infrequently in patients' metabolic charts. Episodes of metabolic decompensation were identifiable but required an operational definition based on acute manifestations most commonly recorded in the metabolic chart. Deaths occurred rarely in these patients and quality of mortality data was not evaluated.
    CONCLUSIONS: Opportunities to record core outcomes at the metabolic clinic occur at least annually for children with MCAD deficiency. Methods to comprehensively capture emergency care received at outside institutions are needed. To reduce substantial heterogeneous recording of core outcome across treatment centres, improved documentation standards are required for recording of recommended fasting times and a consensus definition for metabolic decompensations needs to be developed and implemented.
    Keywords:  Core outcome set; Data quality; MCAD deficiency
    DOI:  https://doi.org/10.1186/s12887-023-04393-4
  48. Cell Rep. 2024 Jan 10. pii: S2211-1247(23)01599-1. [Epub ahead of print]43(1): 113587
    The mitochondrial genome-encoded peptide MOTS-c interacts with Bcl-2 to alleviate nonalcoholic steatohepatitis progression.
    Huanyu Lu, Linni Fan, Wenli Zhang, Guo Chen, An Xiang, Li Wang, Zifan Lu, Yue Zhai.
      Nonalcoholic steatohepatitis (NASH) is a metabolism-associated fatty liver disease with accumulated mitochondrial stress, and targeting mitochondrial function is a potential therapy. The mitochondrial genome-encoded bioactive peptide MOTS-c plays broad physiological roles, but its effectiveness and direct targets in NASH treatment are still unclear. Here, we show that long-term preventive and short-term therapeutic effects of MOTS-c treatments alleviate NASH-diet-induced liver steatosis, cellular apoptosis, inflammation, and fibrosis. Mitochondrial oxidative capacity and metabolites profiling analysis show that MOTS-c significantly reverses NASH-induced mitochondrial metabolic deficiency. Moreover, we identify that MOTS-c directly interacts with the BH3 domain of antiapoptotic B cell lymphoma-2 (Bcl-2), increases Bcl-2 protein stability, and suppresses Bcl-2 ubiquitination. By using a Bcl-2 inhibitor or adeno-associated virus (AAV)-mediated Bcl-2 knockdown, we further confirm that MOTS-c improves NASH-induced mitochondrial dysfunction, inflammation, and fibrosis, which are dependent on Bcl-2 function. Therefore, our findings show that MOTS-c is a potential therapeutic agent to inhibit the progression of NASH.
    Keywords:  Bcl-2; CP: Metabolism; CP: Molecular biology; MOTS-c; apoptosis; mitochondrial dysfunction; nonalcoholic steatohepatitis
    DOI:  https://doi.org/10.1016/j.celrep.2023.113587
  49. Exp Neurol. 2024 Jan 08. pii: S0014-4886(24)00010-4. [Epub ahead of print] 114684
    Insights into neuroinflammatory mechanisms of deep brain stimulation in Parkinson's disease.
    Pinar Eser, Ersoy Kocabicak, Ahmet Bekar, Yasin Temel.
      Parkinson's disease, a progressive neurodegenerative disorder, involves gradual degeneration of the nigrostriatal dopaminergic pathway, leading to neuronal loss within the substantia nigra pars compacta and dopamine depletion. Molecular factors, including neuroinflammation, impaired protein homeostasis, and mitochondrial dysfunction, contribute to the neuronal loss. Deep brain stimulation, a form of neuromodulation, applies electric current through stereotactically implanted electrodes, effectively managing motor symptoms in advanced Parkinson's disease patients. Deep brain stimulation exerts intricate effects on neuronal systems, encompassing alterations in neurotransmitter dynamics, microenvironment restoration, neurogenesis, synaptogenesis, and neuroprotection. Contrary to initial concerns, deep brain stimulation demonstrates antiinflammatory effects, influencing cytokine release, glial activation, and neuronal survival. This review investigates the intricacies of deep brain stimulation mechanisms, including insertional effects, histological changes, and glial responses, and sheds light on the complex interplay between electrodes, stimulation, and the brain. This exploration delves into understanding the role of neuroinflammatory pathways and the effects of deep brain stimulation in the context of Parkinson's disease, providing insights into its neuroprotective capabilities.
    Keywords:  Deep brain stimulation; Insertional effect; Neuroinflammation; Parkinson's disease
    DOI:  https://doi.org/10.1016/j.expneurol.2024.114684
  50. Int J Mol Sci. 2023 Dec 22. pii: 219. [Epub ahead of print]25(1):
    Berberine Induces Mitophagy through Adenosine Monophosphate-Activated Protein Kinase and Ameliorates Mitochondrial Dysfunction in PINK1 Knockout Mouse Embryonic Fibroblasts.
    Jee-Hyun Um, Kang-Min Lee, Young-Yeon Kim, Da-Ye Lee, Eunmi Kim, Dong-Hyun Kim, Jeanho Yun.
      Mitophagy stimulation has been shown to have a therapeutic effect on various neurodegenerative diseases. However, nontoxic mitophagy inducers are still very limited. In this study, we found that the natural alkaloid berberine exhibited mitophagy stimulation activity in various human cells. Berberine did not interfere with mitochondrial function, unlike the well-known mitophagy inducer carbonyl cyanide m-chlorophenyl hydrazone (CCCP), and subsequently induced mitochondrial biogenesis. Berberine treatment induced the activation of adenosine monophosphate-activated protein kinase (AMPK), and the AMPK inhibitor compound C abolished berberine-induced mitophagy, suggesting that AMPK activation is essential for berberine-induced mitophagy. Notably, berberine treatment reversed mitochondrial dysfunction in PINK1 knockout mouse embryonic fibroblasts. Our results suggest that berberine is a mitophagy-specific inducer and can be used as a therapeutic treatment for neurodegenerative diseases, including Parkinson's disease, and that natural alkaloids are potential sources of mitophagy inducers.
    Keywords:  Parkinson’s disease; berberine; mitochondrial dysfunction; mitophagy
    DOI:  https://doi.org/10.3390/ijms25010219
  51. Front Aging Neurosci. 2023 ;15 1326127
    O-GlcNAc regulates the mitochondrial integrated stress response by regulating ATF4.
    Ibtihal M Alghusen, Marisa S Carman, Heather Wilkins, Sophiya John Ephrame, Amy Qiang, Wagner B Dias, Halyna Fedosyuk, Aspin R Denson, Russell H Swerdlow, Chad Slawson.
       Background: Accumulation of mitochondrial dysfunctional is a hallmark of age-related neurodegeneration including Alzheimer's disease (AD). Impairment of mitochondrial quality control mechanisms leading to the accumulation of damaged mitochondria and increasing neuronal stress. Therefore, investigating the basic mechanisms of how mitochondrial homeostasis is regulated is essential. Herein, we investigate the role of O-GlcNAcylation, a single sugar post-translational modification, in controlling mitochondrial stress-induced transcription factor Activating Transcription Factor 4 (ATF4). Mitochondrial dysfunction triggers the integrated stress response (ISRmt), in which the phosphorylation of eukaryotic translation initiation factor 2α results in the translation of ATF4.
    Methods: We used patient-derived induced pluripotent stem cells, a transgenic mouse model of AD, SH-SY5Y neuroblastoma and HeLa cell-lines to examine the effect of sustained O-GlcNAcase inhibition by Thiamet-G (TMG) on ISRmt using biochemical analyses.
    Results: We show that TMG elevates ATF4 protein levels upon mitochondrial stress in SH-SY5Y neuroblastoma and HeLa cell-lines. An indirect downstream target of ATF4 mitochondrial chaperone glucose-regulated protein 75 (GRP75) is significantly elevated. Interestingly, knock-down of O-GlcNAc transferase (OGT), the enzyme that adds O-GlcNAc, in SH-SY5Y increases ATF4 protein and mRNA expression. Additionally, ATF4 target gene Activating Transcription Factor 5 (ATF5) is significantly elevated at both the protein and mRNA level. Brains isolated from TMG treated mice show elevated levels of ATF4 and GRP75. Importantly, ATF4 occupancy increases at the ATF5 promoter site in brains isolated from TMG treated mice suggesting that O-GlcNAc is regulating ATF4 targeted gene expression. Interestingly, ATF4 and GRP75 are not induced in TMG treated familial Alzheimer's Disease mice model. The same results are seen in a human in vitro model of AD.
    Conclusion: Together, these results indicate that in healthy conditions, O-GlcNAc regulates the ISRmt through regulating ATF4, while manipulating O-GlcNAc in AD has no effect on ISRmt.
    Keywords:  Alzheimer’s disease; O-GlcNAc; activating transcription factor 4 (ATF4); integrated stress response; mitochondrial stress
    DOI:  https://doi.org/10.3389/fnagi.2023.1326127
  52. Biogerontology. 2024 Jan 06.
    Age and dietary restriction modulate mitochondrial quality in quadriceps femoris muscle of male mice.
    Ting-Rui Zhang, Chun-Hsien Chiang, Tzu-Chieh Hsu, Chih-Yun Wang, Ching-Yi Chen.
      Dietary restriction (DR) is a potential intervention for ameliorating ageing-related damages. Mitochondrial quality control is the key mechanism for regulating cellular functions in skeletal muscle. This study aimed to explore the effect of age and DR on the homeostasis of mitochondrial quality control in skeletal muscle. To study the effect of age on mitochondrial homeostasis, young (3 months old) male C57BL/6J mice were fed ad libitum (AL) until 7 (Young), 14 (Middle), and 19 months (Aged) of age. For the DR intervention, 60% of AL intake was given to the mice at 3 months of age until they reached 19 months of age (16 months). The quadriceps femoris muscle was collected for further analysis. Significant changes in the skeletal muscle were noticed during the transition between middle age and the elderly stages. An accumulation of collagen was observed in the muscle after middle age. Compared with the Middle muscle, Aged muscle displayed a greater expression of VDAC, and lower expressions of mitochondrial dynamic proteins and OXPHOS proteins. The DR intervention attenuated collagen content and elongated the sarcomere length in the skeletal muscle during ageing. In addition, DR adjusted the abnormalities in mitochondrial morphology in the Aged muscle. DR downregulated VDAC expression, but upregulated OPA1 and DRP1 expressions. Taken together, greater pathological changes were noticed in the skeletal muscle during ageing, especially in the transition between middle age and the elderly, whereas early-onset DR attenuated the muscular ageing via normalising partial functions of mitochondria.
    Keywords:  Ageing; Dietary restriction; Mitochondrial homeostasis; Quadriceps femoris muscle
    DOI:  https://doi.org/10.1007/s10522-023-10086-3
  53. JIMD Rep. 2024 Jan;65(1): 10-16
    Pyruvate carboxylase deficiency type C; variable presentation and beneficial effect of triheptanoin.
    I Bernhardt, L Van Dorp, M Dixon, M McSweeney, C Gan, J Baruteau, A Chakrapani.
      Pyruvate carboxylase is a mitochondrial enzyme essential for the tricarboxylic acid cycle (TCA), gluconeogenesis and fatty-acid synthesis. Pyruvate carboxylase deficiency (PCD) mostly presents with life-limiting encephalopathy (types A/B). A milder type C presentation is rare, with a comparatively favourable prognosis. Therapies remain essentially supportive. Triheptanoin is an odd-chain triglyceride, with the potential to replenish TCA intermediates (anaplerosis), and its metabolites cross the blood-brain-barrier. Outcomes of triheptanoin treatment in PCD types A/B have been disappointing, but have not been reported in type C. Here, we present two new patients with PCD type C, and report the response to treatment with triheptanoin in one. Patient 1 (P1) presented with neonatal-onset lactic acidosis and recurrent symptomatic lactic acidosis following exercise and during illnesses, with frequent hospitalisations. Speech development was delayed. MRI-brain showed delayed cerebral myelination. Patient 2 (P2) presented with episodic ketoacidosis, hyperlactataemia and hypoglycaemia at 2 years of age, with gross motor delay and mild global volume loss on MRI brain. Treatment with triheptanoin was commenced in P1 at 3 years of age with up-titration to 35 mL/day (25% of daily energy intake) over 6 months, due to transient diarrhoea. Dietary long-chain triglycerides were restricted, with fat-soluble vitamin supplementation. Subsequently, hospitalisations during intercurrent illnesses decreased, post-exertional hyperlactataemia resolved and exercise tolerance improved. Continued developmental progress was observed, and repeat MRI 18 months after initiation showed improved myelination. Triheptanoin was well-tolerated and appeared efficacious during 2 years' follow-up, and has potential to restore energy homeostasis and myelin synthesis in PCD type C.
    DOI:  https://doi.org/10.1002/jmd2.12405
  54. bioRxiv. 2023 Dec 19. pii: 2023.12.19.572332. [Epub ahead of print]
    A new GUV-based assay to reconstitute membrane tethering in vitro demonstrates the vesicle tethering ability of the selective autophagy scaffold Atg11.
    Devika Andhare, Michael J Ragusa.
      Membrane tethering is essential for the generation of organelle contact sites and to anchor incoming vesicles to their target membranes before vesicle fusion. During autophagy in yeast, tethering of 30 nm vesicles to cargo is one of the first steps in the generation of the isolation membrane that engulfs the cargo to be degraded. While membrane tethering is critical for cellular function, many of the current biochemical techniques to assay for membrane tethering rely on indirect readouts and are limited in their ability to monitor protein localization at sites of tethering. As such, we developed a fluorescence-microscopy-based G UV liposome tethering assay (GLT) to directly visualize membrane tethering and monitor protein localization at tethering sites simultaneously. We initially used GLT with engineered membrane tethers to demonstrate the ease of use, versatility and sensitivity of the assay. We also demonstrated that the selective autophagy scaffolding protein Atg11 can bind, and tether negatively charged membranes but is unable to bind GUVs mimicking the charge of the outer mitochondrial membrane. Atg11 instead requires the selective autophagy receptor Atg32 to be recruited to mitochondrial membranes. Lastly, we demonstrate that Atg11 bound to Atg32 on GUVs can tether negatively charged vesicles to GUVs. Collectively, our results reconstitute one of the first steps during the initiation of mitochondrial autophagy and highlight the versatility of GLT to study a range of membrane tethering events biochemically.
    DOI:  https://doi.org/10.1101/2023.12.19.572332
  55. Food Nutr Res. 2023 ;67
    Niacin - a scoping review for Nordic Nutrition Recommendations 2023.
    Riitta Freese, Vegard Lysne.
      Niacin is the precursor to pyridine nucleotides NAD (nicotinamide adenine dinucleotide) and NADP (nicotinamide adenine dinucleotide phosphate). Niacin (vitamin B3) is the common term for nicotinic acid, nicotinamide and derivatives that exhibit the biological activity of nicotinamide. Furthermore, the indispensable amino acid tryptophan is the substrate for de novo synthesis of NAD. Thus, the requirements and intake of niacin are expressed as niacin equivalents (NE). The focus of interest for niacin over the last decade has primarily been on pharmacological doses of nicotinic acid as a lipid-lowering agent and other NAD precursors as potential enhancers of cellular NAD+ concentrations. None of these studies, however, makes a useful contribution to understanding dietary requirements in healthy populations. The requirement for niacin is estimated based on the relationship between intake and biochemical indices of niacin status, primarily urinary excretion of nicotinamide metabolites.
    Keywords:  Nordic countries; niacin; nicotinamide; nicotinamide adenine dinucleotide; nicotinic acid; nutrition recommendation; requirement; tryptophan; vitamin B3
    DOI:  https://doi.org/10.29219/fnr.v67.10299
  56. Nat Aging. 2024 Jan 10.
    TIME-seq reduces time and cost of DNA methylation measurement for epigenetic clock construction.
    Patrick T Griffin, Alice E Kane, Alexandre Trapp, Jien Li, Matthew Arnold, Jesse R Poganik, Ryan J Conway, Maeve S McNamara, Margarita V Meer, Noah Hoffman, João A Amorim, Xiao Tian, Michael R MacArthur, Sarah J Mitchell, Amber L Mueller, Colleen Carmody, Daniel L Vera, Csaba Kerepesi, Kejun Ying, Nicole Noren Hooten, James R Mitchell, Michele K Evans, Vadim N Gladyshev, David A Sinclair.
      Epigenetic 'clocks' based on DNA methylation have emerged as the most robust and widely used aging biomarkers, but conventional methods for applying them are expensive and laborious. Here we develop tagmentation-based indexing for methylation sequencing (TIME-seq), a highly multiplexed and scalable method for low-cost epigenetic clocks. Using TIME-seq, we applied multi-tissue and tissue-specific epigenetic clocks in over 1,800 mouse DNA samples from eight tissue and cell types. We show that TIME-seq clocks are accurate and robust, enriched for polycomb repressive complex 2-regulated loci, and benchmark favorably against conventional methods despite being up to 100-fold less expensive. Using dietary treatments and gene therapy, we find that TIME-seq clocks reflect diverse interventions in multiple tissues. Finally, we develop an economical human blood clock (R > 0.96, median error = 3.39 years) in 1,056 demographically representative individuals. These methods will enable more efficient epigenetic clock measurement in larger-scale human and animal studies.
    DOI:  https://doi.org/10.1038/s43587-023-00555-2
  57. Cell Metab. 2024 Jan 01. pii: S1550-4131(23)00462-X. [Epub ahead of print]
    DMHPpp1r17 neurons regulate aging and lifespan in mice through hypothalamic-adipose inter-tissue communication.
    Kyohei Tokizane, Cynthia S Brace, Shin-Ichiro Imai.
      Recent studies have shown that the hypothalamus functions as a control center of aging in mammals that counteracts age-associated physiological decline through inter-tissue communications. We have identified a key neuronal subpopulation in the dorsomedial hypothalamus (DMH), marked by Ppp1r17 expression (DMHPpp1r17 neurons), that regulates aging and longevity in mice. DMHPpp1r17 neurons regulate physical activity and WAT function, including the secretion of extracellular nicotinamide phosphoribosyltransferase (eNAMPT), through sympathetic nervous stimulation. Within DMHPpp1r17 neurons, the phosphorylation and subsequent nuclear-cytoplasmic translocation of Ppp1r17, regulated by cGMP-dependent protein kinase G (PKG; Prkg1), affect gene expression regulating synaptic function, causing synaptic transmission dysfunction and impaired WAT function. Both DMH-specific Prkg1 knockdown, which suppresses age-associated Ppp1r17 translocation, and the chemogenetic activation of DMHPpp1r17 neurons significantly ameliorate age-associated dysfunction in WAT, increase physical activity, and extend lifespan. Thus, these findings clearly demonstrate the importance of the inter-tissue communication between the hypothalamus and WAT in mammalian aging and longevity control.
    Keywords:  DMH; PKG; Ppp1r17; aging; dorsomedial hypothalamus; eNAMPT; longevity; protein kinase G; sympathetic nervous system; white adipose tissue
    DOI:  https://doi.org/10.1016/j.cmet.2023.12.011
  58. J Hum Genet. 2024 Jan 12.
    Detection of hidden intronic DDC variant in aromatic L-amino acid decarboxylase deficiency by adaptive sampling.
    Eriko Koshimizu, Mitsuhiro Kato, Kazuharu Misawa, Yuri Uchiyama, Naomi Tsuchida, Kohei Hamanaka, Atsushi Fujita, Takeshi Mizuguchi, Satoko Miyatake, Naomichi Matsumoto.
      Aromatic l-amino acid decarboxylase (AADC) deficiency is an autosomal recessive neurotransmitter disorder caused by pathogenic DOPA decarboxylase (DDC) variants. We previously reported Japanese siblings with AADC deficiency, which was confirmed by the lack of enzyme activity; however, only a heterozygous missense variant was detected. We therefore performed targeted long-read sequencing by adaptive sampling to identify any missing variants. Haplotype phasing and variant calling identified a novel deep intronic variant (c.714+255 C > A), which was predicted to potentially activate the noncanonical splicing acceptor site. Minigene assay revealed that wild-type and c.714+255 C > A alleles had different impacts on splicing. Three transcripts, including the canonical transcript, were detected from the wild-type allele, but only the noncanonical cryptic exon was produced from the variant allele, indicating that c.714+255 C > A was pathogenic. Target long-read sequencing may be used to detect hidden pathogenic variants in unresolved autosomal recessive cases with only one disclosed hit variant.
    DOI:  https://doi.org/10.1038/s10038-023-01217-2
  59. Comput Struct Biotechnol J. 2023 ;21 940-955
    A guidebook of spatial transcriptomic technologies, data resources and analysis approaches.
    Liangchen Yue, Feng Liu, Jiongsong Hu, Pin Yang, Yuxiang Wang, Junguo Dong, Wenjie Shu, Xingxu Huang, Shengqi Wang.
      Advances in transcriptomic technologies have deepened our understanding of the cellular gene expression programs of multicellular organisms and provided a theoretical basis for disease diagnosis and therapy. However, both bulk and single-cell RNA sequencing approaches lose the spatial context of cells within the tissue microenvironment, and the development of spatial transcriptomics has made overall bias-free access to both transcriptional information and spatial information possible. Here, we elaborate development of spatial transcriptomic technologies to help researchers select the best-suited technology for their goals and integrate the vast amounts of data to facilitate data accessibility and availability. Then, we marshal various computational approaches to analyze spatial transcriptomic data for various purposes and describe the spatial multimodal omics and its potential for application in tumor tissue. Finally, we provide a detailed discussion and outlook of the spatial transcriptomic technologies, data resources and analysis approaches to guide current and future research on spatial transcriptomics.
    Keywords:  Spatial transcriptomic technologies
    DOI:  https://doi.org/10.1016/j.csbj.2023.01.016
  60. Comput Biol Med. 2024 Jan 03. pii: S0010-4825(24)00009-X. [Epub ahead of print]169 107925
    DL-SPhos: Prediction of serine phosphorylation sites using transformer language model.
    Palistha Shrestha, Jeevan Kandel, Hilal Tayara, Kil To Chong.
      Serine phosphorylation plays a pivotal role in the pathogenesis of various cellular processes and diseases. Roughly 81% of human diseases have links to phosphorylation, and an overwhelming 86.4% of protein phosphorylation takes place at serine residues. In eukaryotes, over a quarter of proteins undergo phosphorylation, with more than half implicated in numerous disorders, notably cancer and reproductive system diseases. This study primarily focuses on serine-phosphorylation-driven pathogenesis and the critical role of conserved motif identification. While numerous techniques exist for predicting serine phosphorylation sites, traditional wet lab experiments are resource-intensive. Our paper introduces a cutting-edge deep learning tool for predicting S phosphorylation sites, integrating explainable AI for motif identification, a transformer language model, and deep neural network components. We trained our model on protein sequences from UniProt, validated it against the dbPTM benchmark dataset, and employed the PTMD dataset to explore motifs related to mammalian disorders. Our results highlight that our model surpasses other deep learning predictors by a significant 3%. Furthermore, we utilized the local interpretable model-agnostic explanations (LIME) approach to shed light on the predictions, emphasizing the amino acid residues crucial for S phosphorylation. Notably, our model also outperformed competitors in kinase-specific serine phosphorylation prediction on benchmark datasets.
    Keywords:  Mammalian diseases; Motif identification; Protein sequence; Serine phosphorylation; Transformer language model
    DOI:  https://doi.org/10.1016/j.compbiomed.2024.107925
  61. J Inherit Metab Dis. 2024 Jan 10.
    Glyoxylate reductase: Definitive identification in human liver mitochondria, its importance for the compartment-specific detoxification of glyoxylate.
    Sander F Garrelfs, Serhii Chornyi, Heleen Te Brinke, Jos Ruiter, Jaap Groothoff, Ronald J A Wanders.
      Glyoxylate is a key metabolite generated from various precursor substrates in different subcellular compartments including mitochondria, peroxisomes, and the cytosol. The fact that glyoxylate is a good substrate for the ubiquitously expressed enzyme lactate dehydrogenase (LDH) requires the presence of efficient glyoxylate detoxification systems to avoid the formation of oxalate. Furthermore, this detoxification needs to be compartment-specific since LDH is actively present in multiple subcellular compartments including peroxisomes, mitochondria, and the cytosol. Whereas the identity of these protection systems has been established for both peroxisomes and the cytosol as concluded from the deficiency of alanine glyoxylate aminotransferase (AGT) in primary hyperoxaluria type 1 (PH1) and glyoxylate reductase (GR) in PH2, the glyoxylate protection system in mitochondria has remained less well defined. In this manuscript, we show that the enzyme glyoxylate reductase has a bimodal distribution in human embryonic kidney (HEK293), hepatocellular carcinoma (HepG2), and cervical carcinoma (HeLa) cells and more importantly, in human liver, and is actively present in both the mitochondrial and cytosolic compartments. We conclude that the metabolism of glyoxylate in humans requires the complicated interaction between different subcellular compartments within the cell and discuss the implications for the different primary hyperoxalurias.
    Keywords:  glyoxylate metabolism; hydroxyproline; hyperoxaluria; mitochondria; oxalate; peroxisomal disorders; peroxisomes
    DOI:  https://doi.org/10.1002/jimd.12711
  62. bioRxiv. 2023 Dec 19. pii: 2023.12.18.572285. [Epub ahead of print]
    Cell type-specific enrichment of somatic aneuploidy in the mammalian brain.
    Eran A Mukamel, Hanqing Liu, M Margarita Behrens, Joseph R Ecker.
      Somatic mutations alter the genomes of a subset of an individual's brain cells1-3, impacting gene regulation and contributing to disease processes4,5. Mosaic single nucleotide variants have been characterized with single-cell resolution in the brain2,3, but we have limited information about large-scale structural variation, including whole-chromosome duplication or loss1,6,7. We used a dataset of over 415,000 single-cell DNA methylation and chromatin conformation profiles across the adult mouse brain to identify aneuploid cells comprehensively. Whole-chromosome loss or duplication occurred in <1% of cells, with rates up to 1.8% in non-neuronal cell types, including oligodendrocyte precursors and pericytes. Among all aneuploidies, we observed a strong enrichment of trisomy on chromosome 16, which is syntenic with human chromosome 21 and constitutively trisomic in Down syndrome. Chromosome 16 trisomy occurred in multiple cell types and across brain regions, suggesting that nondisjunction is a recurrent feature of somatic variation in the brain.
    DOI:  https://doi.org/10.1101/2023.12.18.572285
  63. Genet Med. 2024 Jan 06. pii: S1098-3600(24)00001-7. [Epub ahead of print] 101068
    Unbiased phenotype and genotype matching maximizes gene discovery and diagnostic yield.
    Jonathan Rips, Orli Halstuk, Adina Fuchs, Ziv Lang, Tal Sido, Shiri Gershon-Naamat, Bassam Abu-Libdeh, Simon Edvardson, Somaya Salah, Oded Breuer, Mohamad Hadhud, Sharon Eden, Itamar Simon, Mordechai Slae, Nadirah S Damseh, Abdulsalam Abu-Libdeh, Marina Eskin-Schwartz, Ohad S Birk, Julia Varga, Ora Schueler-Furman, Chaggai Rosenbluh, Orly Elpeleg, Shira Yanovsky-Dagan, Hagar Mor-Shaked, Tamar Harel.
       PURPOSE: Widespread application of next-generation sequencing, combined with data exchange platforms, has provided molecular diagnoses for countless families. To maximize diagnostic yield, we implemented an unbiased semi-automated genematching algorithm based on genotype and phenotype matching.
    METHODS: Rare homozygous variants identified in two or more affected individuals, but not in healthy individuals, were extracted from our local database of ∼12,000 exomes. Phenotype similarity scores, based on human phenotype ontology terms, were assigned to each pair of individuals matched at the genotype level using HPOsim.
    RESULTS: 33,792 genotype-matched pairs were discovered, representing variants in 7,567 unique genes. There was an enrichment of phenotype similarity scores ≥0.1 amongst pathogenic/likely pathogenic variant-level pairs (94.3% in P/LP variant-level matches vs. 34.75% in all matches). We highlighted founder or region-specific variants as an internal positive control, and proceeded to identify candidate disease genes. Variant-level matches were particularly helpful in cases involving inframe indels and splice region variants beyond the canonical splice sites, which may otherwise have been disregarded, allowing for detection of candidate disease genes such as KAT2A, RPAIN, and LAMP3.
    CONCLUSION: Semi-automated genotype matching combined with phenotype similarity scores is a powerful tool to resolve variants of uncertain significance and to identify candidate disease genes.
    Keywords:  exome sequencing; genotype matching; phenotype similarity scores; variants of uncertain significance
    DOI:  https://doi.org/10.1016/j.gim.2024.101068
  64. Eur J Hum Genet. 2024 Jan 12.
    Reanalysis of genomic data, how do we do it now and what if we automate it? A qualitative study.
    Zoe Fehlberg, Zornitza Stark, Stephanie Best.
      Automating reanalysis of genomic data for undiagnosed rare disease patients presents a paradigm shift in how clinical genomics is delivered. We aimed to map the current manual and proposed automated approach to reanalysis and identify possible implementation strategies to address clinical and laboratory staff's perceived challenges to automation. Fourteen semi-structured interviews guided by a simplified process map were conducted with clinical and laboratory staff across Australia. Individual process maps were integrated into an overview of the current process, noting variation in service delivery. Participants then mapped an automated approach and were invited to discuss perceived challenges and possible supports to automation. Responses were analysed using the Consolidated Framework for Implementation Research, linking to the Expert Recommendations for Implementing Change framework to identify theory-informed implementation strategies. Process mapping demonstrates how automation streamlines processes with eleven steps reduced to seven. Although participants welcomed automation, challenges were raised at six of the steps. Strategies to overcome challenges include embedding project champions, developing education materials, facilitating clinical innovation and quality monitoring tools, and altering reimbursement structures. Future work can build on these findings to develop context specific implementation strategies to guide translation of an automated approach to reanalysis to improve clinical care and patient outcomes.
    DOI:  https://doi.org/10.1038/s41431-023-01532-4
  65. J Neurol Sci. 2024 Jan 03. pii: S0022-510X(23)02332-8. [Epub ahead of print]457 122863
    Cockayne syndrome: A pediatric neurodegenerative disorder linking mitochondria to aging.
    Mary Kate Hatch, Colleen Donnelly, Pankaj Prasun.
      
    Keywords:  Aging; Cockayne syndrome; DNA repair; Mitochondria; Neurodegeneration
    DOI:  https://doi.org/10.1016/j.jns.2023.122863
  66. Redox Biol. 2024 Jan 03. pii: S2213-2317(23)00419-6. [Epub ahead of print]69 103018
    Longevity control by supersulfide-mediated mitochondrial respiration and regulation of protein quality.
    Akira Nishimura, Sunghyeon Yoon, Tetsuro Matsunaga, Tomoaki Ida, Minkyung Jung, Seiryo Ogata, Masanobu Morita, Jun Yoshitake, Yuka Unno, Uladzimir Barayeu, Tsuyoshi Takata, Hiroshi Takagi, Hozumi Motohashi, Albert van der Vliet, Takaaki Akaike.
      Supersulfides, which are defined as sulfur species with catenated sulfur atoms, are increasingly being investigated in biology. We recently identified pyridoxal phosphate (PLP)-dependent biosynthesis of cysteine persulfide (CysSSH) and related supersulfides by cysteinyl-tRNA synthetase (CARS). Here, we investigated the physiological role of CysSSH in budding yeast (Saccharomyces cerevisiae) by generating a PLP-binding site mutation K109A in CRS1 (the yeast ortholog of CARS), which decreased the synthesis of CysSSH and related supersulfides and also led to reduced chronological aging, effects that were associated with an increased endoplasmic reticulum stress response and impaired mitochondrial bioenergetics. Reduced chronological aging in the K109A mutant could be rescued by using exogenous supersulfide donors. Our findings indicate important roles for CARS in the production and metabolism of supersulfides-to mediate mitochondrial function and to regulate longevity.
    Keywords:  Cysteinyl-tRNA synthetase; ER stress; Longevity; Mitochondrial energy metabolism; Supersulfides
    DOI:  https://doi.org/10.1016/j.redox.2023.103018
  67. Clin Genet. 2024 Jan 09.
    Further delineation of the phenotypic and metabolomic profile of ALDH1L2-related neurodevelopmental disorder.
    Mikyoung You, Hanan E Shamseldin, Halle M Fogle, Blake R Rushing, Reem H AlMalki, Amal Jaafar, Mais Hashem, Firdous Abdulwahab, Anas M Abdel Rahman, Natalia I Krupenko, Fowzan S Alkuraya, Sergey A Krupenko.
      ALDH1L2, a mitochondrial enzyme in folate metabolism, converts 10-formyl-THF (10-formyltetrahydrofolate) to THF (tetrahydrofolate) and CO2 . At the cellular level, deficiency of this NADP+ -dependent reaction results in marked reduction in NADPH/NADP+ ratio and reduced mitochondrial ATP. Thus far, a single patient with biallelic ALDH1L2 variants and the phenotype of a neurodevelopmental disorder has been reported. Here, we describe another patient with a neurodevelopmental disorder associated with a novel homozygous missense variant in ALDH1L2, Pro133His. The variant caused marked reduction in the ALDH1L2 enzyme activity in skin fibroblasts derived from the patient as probed by 10-FDDF, a stable synthetic analog of 10-formyl-THF. Additional associated abnormalities in these fibroblasts include reduced NADPH/NADP+ ratio and pool of mitochondrial ATP, upregulated autophagy and dramatically altered metabolomic profile. Overall, our study further supports a link between ALDH1L2 deficiency and abnormal neurodevelopment in humans.
    Keywords:  ALDH1L2; folate metabolism; metabolomics; missense mutation; neurodevelopmental disorder
    DOI:  https://doi.org/10.1111/cge.14479
  68. Hepatobiliary Pancreat Dis Int. 2023 Dec 30. pii: S1499-3872(23)00246-1. [Epub ahead of print]
    Mitochondrial dysfunction in the pathogenesis of acute pancreatitis.
    Xia Chen, Rui Zhong, Bing Hu.
      The mechanism of cell damage during acute pancreatitis (AP) has not been fully elucidated, and there is still a lack of specific or effective treatments. Increasing evidence has implicated mitochondrial dysfunction as a key event in the pathophysiology of AP. Mitochondrial dysfunction is closely related to calcium (Ca2+) overload, intracellular adenosine triphosphate depletion, mitochondrial permeability transition pore openings, loss of mitochondrial membrane potential, mitophagy damage and inflammatory responses. Mitochondrial dysfunction is an early triggering event in the initiation and development of AP, and this organelle damage may precede the release of inflammatory cytokines, intracellular trypsin activation and vacuole formation of pancreatic acinar cells. This review provides further insight into the role of mitochondria in both physiological and pathophysiological aspects of AP, aiming to improve our understanding of the underlying mechanism which may lead to the development of therapeutic and preventive strategies for AP.
    Keywords:  Acute pancreatitis; Autophagy; Calcium; Cell death; Inflammation; Mitochondria; Mitophagy
    DOI:  https://doi.org/10.1016/j.hbpd.2023.12.008
  69. JAMA Intern Med. 2024 Jan 08.
    Protecting Patients by Reducing Diagnostic Error.
    Grace Y Zhang, Cary P Gross.
      
    DOI:  https://doi.org/10.1001/jamainternmed.2023.7334
  70. Sci China Life Sci. 2024 Jan 04.
    Stay in touch with the endoplasmic reticulum.
    Sha Sun, Gan Zhao, Mingkang Jia, Qing Jiang, Shulin Li, Haibin Wang, Wenjing Li, Yunyun Wang, Xin Bian, Yan G Zhao, Xun Huang, Ge Yang, Huaqing Cai, Jose C Pastor-Pareja, Liang Ge, Chuanmao Zhang, Junjie Hu.
      The endoplasmic reticulum (ER), which is composed of a continuous network of tubules and sheets, forms the most widely distributed membrane system in eukaryotic cells. As a result, it engages a variety of organelles by establishing membrane contact sites (MCSs). These contacts regulate organelle positioning and remodeling, including fusion and fission, facilitate precise lipid exchange, and couple vital signaling events. Here, we systematically review recent advances and converging themes on ER-involved organellar contact. The molecular basis, cellular influence, and potential physiological functions for ER/nuclear envelope contacts with mitochondria, Golgi, endosomes, lysosomes, lipid droplets, autophagosomes, and plasma membrane are summarized.
    Keywords:  Golgi apparatus; autophagosome; endoplasmic reticulum; endosome; lipid droplets; lysosome; membrane contact site; mitochondria; nuclear envelope; plasma membrane
    DOI:  https://doi.org/10.1007/s11427-023-2443-9
  71. NPJ Parkinsons Dis. 2024 Jan 08. 10(1): 11
    Analysis of rare Parkinson's disease variants in millions of people.
    23andMe Research Team
      Although many rare variants have been reportedly associated with Parkinson's disease (PD), many have not been replicated or have failed to replicate. Here, we conduct a large-scale replication of rare PD variants. We assessed a total of 27,590 PD cases, 6701 PD proxies, and 3,106,080 controls from three data sets: 23andMe, Inc., UK Biobank, and AMP-PD. Based on well-known PD genes, 834 variants of interest were selected from the ClinVar annotated 23andMe dataset. We performed a meta-analysis using summary statistics of all three studies. The meta-analysis resulted in five significant variants after Bonferroni correction, including variants in GBA1 and LRRK2. Another eight variants are strong candidate variants for their association with PD. Here, we provide the largest rare variant meta-analysis to date, providing information on confirmed and newly identified variants for their association with PD using several large databases. Additionally we also show the complexities of studying rare variants in large-scale cohorts.
    DOI:  https://doi.org/10.1038/s41531-023-00608-8
  72. Pharmacol Res. 2024 Jan 10. pii: S1043-6618(24)00007-0. [Epub ahead of print] 107063
    IUPHAR ECR review: The cGAS-STING pathway: novel functions beyond innate immune and emerging therapeutic opportunities.
    Xu He, Abdalla Wedn, Jian Wang, Yanlun Gu, Hongjin Liu, Juqi Zhang, Zhiqiang Lin, Renpeng Zhou, Xiaocong Pang, Yimin Cui.
      Stimulator of interferon genes (STING) is a crucial innate immune sensor responsible for distinguishing pathogens and cytosolic DNA, mediating innate immune signaling pathways to defend the host. Recent studies have revealed additional regulatory functions of STING beyond its innate immune-related activities, including the regulation of cellular metabolism, DNA repair, cellular senescence, autophagy and various cell deaths. These findings highlight the broader implications of STING in cellular physiology beyond its role in innate immunity. Currently, approximately 10 STING agonists have entered the clinical stage. Unlike inhibitors, which have a maximum inhibition limit, agonists have the potential for infinite amplification. STING signaling is a complex process that requires precise regulation of STING to ensure balanced immune responses and prevent detrimental autoinflammation. Recent research on the structural mechanism of STING autoinhibition and its negative regulation by adaptor protein complex 1 (AP-1) provides valuable insights into its different effects under physiological and pathological conditions, offering a new perspective for developing immune regulatory drugs. Herein, we present a comprehensive overview of the regulatory functions and molecular mechanisms of STING beyond innate immune regulation, along with updated details of its structural mechanisms. We discuss the implications of these complex regulations in various diseases, emphasizing the importance and feasibility of targeting the immunity-dependent or immunity-independent functions of STING. Moreover, we highlight the current trend in drug development and key points for clinical research, basic research, and translational research related to STING.
    Keywords:  STING; STING modulators; cGAS-STING pathway; novel functions; therapeutic
    DOI:  https://doi.org/10.1016/j.phrs.2024.107063
  73. Int J Mol Sci. 2024 Jan 04. pii: 683. [Epub ahead of print]25(1):
    Secretome Analyses Identify FKBP4 as a GBA1-Associated Protein in CSF and iPS Cells from Parkinson's Disease Patients with GBA1 Mutations.
    Rika Kojima, Wojciech Paslawski, Guochang Lyu, Ernest Arenas, Xiaoqun Zhang, Per Svenningsson.
      Mutations in the GBA1 gene increase the risk of developing Parkinson's disease (PD). However, most carriers of GBA1 mutations do not develop PD throughout their lives. The mechanisms of how GBA1 mutations contribute to PD pathogenesis remain unclear. Cerebrospinal fluid (CSF) is used for detecting pathological conditions of diseases, providing insights into the molecular mechanisms underlying neurodegenerative disorders. In this study, we utilized the proximity extension assay to examine the levels of metabolism-linked protein in the CSF from 17 PD patients carrying GBA1 mutations (GBA1-PD) and 17 idiopathic PD (iPD). The analysis of CSF secretome in GBA1-PD identified 11 significantly altered proteins, namely FKBP4, THOP1, GLRX, TXNDC5, GAL, SEMA3F, CRKL, APLP1, LRP11, CD164, and NPTXR. To investigate GBA1-associated CSF changes attributed to specific neuronal subtypes responsible for PD, we analyzed the cell culture supernatant from GBA1-PD-induced pluripotent stem cell (iPSC)-derived midbrain dopaminergic (mDA) neurons. The secretome analysis of GBA1-PD iPSC-derived mDA neurons revealed that five differently regulated proteins overlapped with those identified in the CSF analysis: FKBP4, THOP1, GLRX, GAL, and CRKL. Reduced intracellular level of the top hit, FKPB4, was confirmed via Western Blot. In conclusion, our findings identify significantly altered CSF GBA1-PD-associated proteins with FKPB4 being firmly attributed to mDA neurons.
    Keywords:  FKBP4; GBA1; Parkinson’s disease; cerebrospinal fluid; human-induced pluripotent stem cells (hiPSCs); secretome
    DOI:  https://doi.org/10.3390/ijms25010683
  74. Cell Rep Methods. 2024 Jan 03. pii: S2667-2375(23)00373-9. [Epub ahead of print] 100687
    SIGMA leverages protein structural information to predict the pathogenicity of missense variants.
    Deciphering Disorders Involving Scoliosis & Comorbidities (DISCO) Study
      Leveraging protein structural information to evaluate pathogenicity has been hindered by the scarcity of experimentally determined 3D protein. With the aid of AlphaFold2 predictions, we developed the structure-informed genetic missense mutation assessor (SIGMA) to predict missense variant pathogenicity. In comparison with existing predictors across labeled variant datasets and experimental datasets, SIGMA demonstrates superior performance in predicting missense variant pathogenicity (AUC = 0.933). We found that the relative solvent accessibility of the mutated residue contributed greatly to the predictive ability of SIGMA. We further explored combining SIGMA with other top-tier predictors to create SIGMA+, proving highly effective for variant pathogenicity prediction (AUC = 0.966). To facilitate the application of SIGMA, we pre-computed SIGMA scores for over 48 million possible missense variants across 3,454 disease-associated genes and developed an interactive online platform (https://www.sigma-pred.org/). Overall, by leveraging protein structure information, SIGMA offers an accurate structure-based approach to evaluating the pathogenicity of missense variants.
    Keywords:  CP: Genetics; CP: Systems biology; machine learning; missense variant; protein structure; variant effect predictor
    DOI:  https://doi.org/10.1016/j.crmeth.2023.100687
  75. Am J Med Genet A. 2024 Jan 12.
    Progressive encephalopathy after routine 4-month immunizations in a patient with NAXD genetic variant.
    Marissa Cepress, Ethan Grund, Tomas Leng, Marc Patterson, Mariya Saify, Nessa Aghazadeh Mohandesi, Jason Homme.
      Metabolic pathways are known to generate byproducts-some of which have no clear metabolic function and some of which are toxic. Nicotinamide adenine dinucleotide phosphate hydrate (NAD(P)HX) is a toxic metabolite that is produced by stressors such as a fever, infection, or physical stress. Nicotinamide adenine dinucleotide phosphate hydrate dehydratase (NAXD) and nicotinamide adenine dinucleotide phosphate hydrate epimerase (NAXE) are part of the nicotinamide repair system that function to break down this toxic metabolite. Deficiency of NAXD and NAXE interrupts the critical intracellular repair of NAD(P)HX and allows for its accumulation. Clinically, deficiency of NAXE manifests as progressive, early onset encephalopathy with brain edema and/or leukoencephalopathy (PEBEL) 1, while deficiency of NAXD manifests as PEBEL2. In this report, we describe a case of probable PEBEL2 in a patient with a variant of unknown significance (c.362C>T, p.121L) in the NAXD gene who presented after routine immunizations with significant skin findings and in the absence of fevers.
    Keywords:  NAD(P)HX; NAXD; PEBEL; encephalopathy; metabolite; variant
    DOI:  https://doi.org/10.1002/ajmg.a.63519
  76. Heliyon. 2024 Jan 15. 10(1): e23671
    Newborn screening for fatty acid oxidation disorders in a southern Chinese population.
    Yiming Lin, Chunmei Lin, Bangbang Lin, Zhenzhu Zheng, Weihua Lin, Yanru Chen, Dongmei Chen, Weilin Peng.
       Background and aims: Fatty acid oxidation disorders (FAODs) are a group of autosomal recessive metabolic diseases included in many newborn screening (NBS) programs, but the incidence and disease spectrum vary widely between ethnic groups. We aimed to elucidate the incidence, disease spectrum, and genetic features of FAODs in a southern Chinese population.
    Materials and methods: The FAODs screening results of 643,606 newborns from 2014 to 2022 were analyzed.
    Results: Ninety-two patients were eventually diagnosed with FAODs, of which 61 were PCD, 20 were MADD, 5 were SCADD, 4 were VLCADD, and 2 were CPT-IAD. The overall incidence of FAODs was 1:6996 (95 % CI: 1:5814-1:8772) newborns. All PCD patients had low C0 levels during NBS, while nine patients (14.8 %) had normal C0 levels during the recall review. All but one MADD patients had elevated C8, C10, and C12 levels during NBS, while eight patients (40 %) had normal acylcarnitine levels during the recall review. The most frequent SLC22A5 variant was c.760C > T (p.R254*) with an allele frequency of 29.51 %, followed by c.51C > G (p.F17L) (17.21 %) and c.1400C > G (p.S467C) (16.39 %). The most frequent ETFDH variant was c.250G > A (p.A84T) with an allelic frequency of 47.5 %, followed by c.524G > A (R175H) (12.5 %), c.998A > G (p.Y333C) (12.5 %), and c.1657T > C (p.Y553H) (7.5 %).
    Conclusion: The prevalence, disease spectrum, and genetic characteristics of FAODs in a southern Chinese population were clarified. PCD was the most common FAOD, followed by MADD. Hotspot variants were found in SLC22A5 and ETFDH genes, while the remaining FAODs showed great molecular heterogeneity. Incorporating second-tier genetic screening is critical for FAODs.
    Keywords:  Fatty acid oxidation disorders; Multiple acyl-CoA dehydrogenase deficiency; Newborn screening; Primary carnitine deficiency; Tandem mass spectrometry
    DOI:  https://doi.org/10.1016/j.heliyon.2023.e23671
  77. Sci Transl Med. 2023 11;15(720): eadg4775
    Shifting the trajectory of therapeutic development for neurological and psychiatric disorders.
    Dimitri Krainc, William J Martin, Bradford Casey, Frances E Jensen, Sarah Tishkoff, William Z Potter, Steven E Hyman.
      Clinical trials for central nervous system disorders often enroll patients with unrecognized heterogeneous diseases, leading to costly trials that have high failure rates. Here, we discuss the potential of emerging technologies and datasets to elucidate disease mechanisms and identify biomarkers to improve patient stratification and monitoring of disease progression in clinical trials for neuropsychiatric disorders. Greater efforts must be centered on rigorously standardizing data collection and sharing of methods, datasets, and analytical tools across sectors. To address health care disparities in clinical trials, diversity of genetic ancestries and environmental exposures of research participants and associated biological samples must be prioritized.
    DOI:  https://doi.org/10.1126/scitranslmed.adg4775
  78. Cell Rep. 2024 Jan 10. pii: S2211-1247(24)00001-9. [Epub ahead of print]43(1): 113673
    TALK-1-mediated alterations of β-cell mitochondrial function and insulin secretion impair glucose homeostasis on a diabetogenic diet.
    Sarah M Graff, Arya Y Nakhe, Prasanna K Dadi, Matthew T Dickerson, Jordyn R Dobson, Karolina E Zaborska, Chloe E Ibsen, Regan B Butterworth, Nicholas C Vierra, David A Jacobson.
      Mitochondrial Ca2+ ([Ca2+]m) homeostasis is critical for β-cell function and becomes disrupted during the pathogenesis of diabetes. [Ca2+]m uptake is dependent on elevations in cytoplasmic Ca2+ ([Ca2+]c) and endoplasmic reticulum Ca2+ ([Ca2+]ER) release, both of which are regulated by the two-pore domain K+ channel TALK-1. Here, utilizing a novel β-cell TALK-1-knockout (β-TALK-1-KO) mouse model, we found that TALK-1 limited β-cell [Ca2+]m accumulation and ATP production. However, following exposure to a high-fat diet (HFD), ATP-linked respiration, glucose-stimulated oxygen consumption rate, and glucose-stimulated insulin secretion (GSIS) were increased in control but not TALK1-KO mice. Although β-TALK-1-KO animals showed similar GSIS before and after HFD treatment, these mice were protected from HFD-induced glucose intolerance. Collectively, these data identify that TALK-1 channel control of β-cell function reduces [Ca2+]m and suggest that metabolic remodeling in diabetes drives dysglycemia.
    Keywords:  CP: Cell biology; CP: Metabolism; K2P; TALK-1; calcium handling; diabetes; endoplasmic reticulum; insulin secretion; metabolism; mitochondria; pancreatic β-cell; two-pore-domain potassium channel
    DOI:  https://doi.org/10.1016/j.celrep.2024.113673
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